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Onimaru H, Koyanagi Y, Iigaya K, Ikeda K, Izumizaki M. Intrinsic responses to hypoxia and hypercapnia of neurons in the cardiorespiratory center of the ventral medulla of newborn rats. Pflugers Arch 2025:10.1007/s00424-025-03077-5. [PMID: 40119920 DOI: 10.1007/s00424-025-03077-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 02/21/2025] [Accepted: 03/09/2025] [Indexed: 03/25/2025]
Abstract
The rostral ventrolateral medulla (RVLM) includes a variety of neurons essential for cardiorespiratory control. Although some of these neurons are thought to be intrinsically sensitive to hypercapnia and/or hypoxia, relationships between types of neurons and responses to hypoxia and/or hypercapnia are not well understood. Tyrosine hydroxylase (TH) is one of the cell-type markers of the RVLM neurons. Here, we report effects of hypoxia and hypercapnia on TH-positive or -negative neurons in the RVLM of newborn rats. Brainstem-spinal cord preparations were isolated from 0-3-day-old Wistar rats and superfused with artificial cerebrospinal fluid equilibrated with 95% O2 and 5% CO2, pH 7.4 at 25-26 °C. Membrane potential responses to hypoxia (95% → 0% O2) and/or hypercapnia (2% → 8% CO2) were examined in the presence of tetrodotoxin (TTX) after identification of the firing pattern. We found that TH-positive C1 neurons in the RVLM were sensitive to hypoxia with membrane depolarization but less sensitive to hypercapnia. TH-negative neurons in the C1 area showed responses similar to those of C1 neurons. Moreover, C1 area neurons remained depolarized by hypoxia in the presence of TTX plus gliotransmitter blockers. In contrast, Phox2b-positive and TH-negative neurons in the parafacial respiratory group were intrinsically sensitive to CO2 but not sensitive to hypoxia. Respiratory-related neurons (Phox2b and TH negative) showed a variable response to hypoxia: unchanging, depolarizing, or hyperpolarizing. Our findings suggest that C1 area neurons in the RVLM are intrinsically sensitive to hypoxia and belong to one of the elements constituting central hypoxic sensors.
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Affiliation(s)
- Hiroshi Onimaru
- Department of Physiology, Showa University School of Medicine, Tokyo, 142-8555, Japan.
| | - Yui Koyanagi
- Department of Physiology, Showa University School of Medicine, Tokyo, 142-8555, Japan
| | - Kamon Iigaya
- Department of Physiology, Showa University School of Medicine, Tokyo, 142-8555, Japan
| | - Keiko Ikeda
- Department of Oral Physiology, Showa University School of Dentistry, Tokyo, Japan
| | - Masahiko Izumizaki
- Department of Physiology, Showa University School of Medicine, Tokyo, 142-8555, Japan
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2
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Pathak T, Benson JC, Tang PW, Trebak M, Hempel N. Crosstalk between calcium and reactive oxygen species signaling in cancer revisited. Cell Calcium 2025; 127:103014. [PMID: 40139005 DOI: 10.1016/j.ceca.2025.103014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 03/10/2025] [Accepted: 03/17/2025] [Indexed: 03/29/2025]
Abstract
The homeostasis of cellular reactive oxygen species (ROS) and calcium (Ca2+) are intricately linked. ROS signaling and Ca2+ signaling are reciprocally regulated within cellular microdomains and are crucial for transcription, metabolism and cell function. Tumor cells often highjack ROS and Ca2+ signaling mechanisms to ensure optimal cell survival and tumor progression. Expression and regulation of Ca2+ channels and transporters at the plasma membrane, endoplasmic reticulum, mitochondria and other endomembranes are often altered in tumor cells, and this includes their regulation by ROS and reactive nitrogen species (RNS). Likewise, alterations in cellular Ca2+ levels influence the generation and scavenging of oxidants and thus can alter the redox homeostasis of the cell. This interplay can be either beneficial or detrimental to the cell depending on the localization, duration and levels of ROS and Ca2+ signals. At one end of the spectrum, Ca2+ and ROS/RNS can function as signaling modules while at the other end, lethal surges in these species are associated with cell death. Here, we highlight the interplay between Ca2+ and ROS in cancer progression, emphasize the impact of redox regulation on Ca2+ transport mechanisms, and describe how Ca2+ signaling pathways, in turn, can regulate the cellular redox environment.
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Affiliation(s)
- Trayambak Pathak
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - J Cory Benson
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Priscilla W Tang
- UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medicine, Division of Malignant Hematology & Medical Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mohamed Trebak
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| | - Nadine Hempel
- Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medicine, Division of Malignant Hematology & Medical Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
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3
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Chen S, Takahashi N, Okahara M, Kashiwadani H, Mori Y, Hao L, Kuwaki T. TRPA1 contributes to respiratory depression from tobacco aerosol. Respir Physiol Neurobiol 2025; 332:104385. [PMID: 39706359 DOI: 10.1016/j.resp.2024.104385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 12/09/2024] [Accepted: 12/16/2024] [Indexed: 12/23/2024]
Abstract
Transient receptor potential ankyrin-1 (TRPA1) is expressed in the trigeminal nerves in the nasal cavity. It detects irritant chemicals such as formalin and acrolein, induces respiratory depression to protect against further inhalation, and elicits avoidance behavior. Although tobacco smoke contains formalin, acrolein, and other irritant chemicals, the possible contribution of TRPA1 to protection against tobacco smoke has yet to be fully understood. In this study, we compared respiratory and behavioral responses to an aerosol of tobacco smoke between TRPA1 conditional knockout mice and the controls. We also compared the effect of aerosols from the smoke of traditional standard tobacco and a recently developed heated tobacco product. As expected, respiratory depression by tobacco aerosol was observed only in the TRPA1 intact mice and was associated with increased trigeminal activation. Meanwhile, mice did not avoid or even prefer tobacco aerosol in a TRPA1-independent manner, contrary to our expectations. Repeated exposure to tobacco aerosol resulted in lung inflammation in a TRPA1-independent manner. Aerosols from a heated tobacco product showed no significant effect as in traditional tobacco smoke. These results indicate that TRPA1 contributes to acute protection from tobacco smoke by inducing respiratory depression but not to the safety of the lungs in repeated exposure. Tobacco aerosol contains attractive substances for mice. Heated tobacco product aerosol contains less TRPA1 activating substances and less inflammation evoking than traditional tobacco smoke.
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Affiliation(s)
- Sichong Chen
- Department of Physiology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan; Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, China
| | - Nobuaki Takahashi
- Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Momoka Okahara
- Department of Physiology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Hideki Kashiwadani
- Department of Physiology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Yasuo Mori
- Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Liying Hao
- Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, China
| | - Tomoyuki Kuwaki
- Department of Physiology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
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4
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Banerjee A, Kumar S, Acharya TK. Mitochondria drive hypoxia tolerance in naked mole rat brain. J Physiol 2024; 602:5723-5725. [PMID: 37934674 DOI: 10.1113/jp285730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2023] Open
Affiliation(s)
- Anushka Banerjee
- Tissue Restoration Lab, Department of Biological Sciences and Bioengineering, The Mehta Family Centre for Engineering in Medicine, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh, India
| | - Satish Kumar
- School of Biological Sciences, National Institute of Science Education and Research Bhubaneswar, Khurda, Odisha, India
- Homi Bhabha National Institute, Training School Complex, Mumbai, India
| | - Tusar Kanta Acharya
- School of Biological Sciences, National Institute of Science Education and Research Bhubaneswar, Khurda, Odisha, India
- Homi Bhabha National Institute, Training School Complex, Mumbai, India
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Kuwaki T, Takahashi N. TRPA1 channel in the airway underlies protection against airborne threats by modulating respiration and behaviour. J Physiol 2024; 602:4755-4762. [PMID: 37147468 DOI: 10.1113/jp284076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 05/02/2023] [Indexed: 05/07/2023] Open
Abstract
Transient receptor potential ankyrin 1 (TRPA1), a member of the TRP superfamily of cation channels, is broadly expressed in sensory neural pathways, including the trigeminal neurons innervating the nasal cavity and vagal neurons innervating the trachea and the lung. TRPA1 acts as a detector of various irritant chemicals as well as hypoxia and hyperoxia. For the past 15 years, we have characterised its role in respiratory and behavioural modulation in vivo using Trpa1 knockout (KO) mice and wild-type (WT) littermates. Trpa1 KO mice failed to detect, wake up from sleeping, and escape from formalin vapour and a mild hypoxic (15% O2) environment. Respiratory augmentation induced by mild hypoxia was absent in either Trpa1 KO mice or WT mice treated with a TRPA1 antagonist. Irritant gas introduced into the nasal cavity inhibited respiratory responses in WT mice but not in the KO mice. The effect of TRPA1 on the olfactory system seemed minimal because olfactory bulbectomized WT mice reacted similarly to the intact mice. Immunohistological analyses using a cellar activation marker, the phosphorylated form of extracellular signal-regulated kinase, confirmed activation of trigeminal neurons in WT mice but not in Trpa1 KO mice in response to irritant chemicals and mild hypoxia. These data collectively show that TRPA1 is necessary for multiple chemical-induced protective responses in respiration and behaviour. We propose that TRPA1 channels in the airway may play a sentinel role for environmental threats and prevent incoming damage.
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Affiliation(s)
- Tomoyuki Kuwaki
- Department of Physiology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Nobuaki Takahashi
- The Hakubi Center for Advanced Research & Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Kyoto, Japan
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6
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Sakaguchi R, Takahashi N, Yoshida T, Ogawa N, Ueda Y, Hamano S, Yamaguchi K, Sawamura S, Yamamoto S, Hara Y, Kawamoto T, Suzuki R, Nakao A, Mori MX, Furukawa T, Shimizu S, Inoue R, Mori Y. Dynamic remodeling of TRPC5 channel-caveolin-1-eNOS protein assembly potentiates the positive feedback interaction between Ca 2+ and NO signals. J Biol Chem 2024; 300:107705. [PMID: 39178948 PMCID: PMC11420454 DOI: 10.1016/j.jbc.2024.107705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 07/25/2024] [Accepted: 08/01/2024] [Indexed: 08/26/2024] Open
Abstract
The cell signaling molecules nitric oxide (NO) and Ca2+ regulate diverse biological processes through their closely coordinated activities directed by signaling protein complexes. However, it remains unclear how dynamically the multicomponent protein assemblies behave within the signaling complexes upon the interplay between NO and Ca2+ signals. Here we demonstrate that TRPC5 channels activated by the stimulation of G-protein-coupled ATP receptors mediate Ca2+ influx, that triggers NO production from endothelial NO synthase (eNOS), inducing secondary activation of TRPC5 via cysteine S-nitrosylation and eNOS in vascular endothelial cells. Mutations in the caveolin-1-binding domains of TRPC5 disrupt its association with caveolin-1 and impair Ca2+ influx and NO production, suggesting that caveolin-1 serves primarily as the scaffold for TRPC5 and eNOS to assemble into the signal complex. Interestingly, during ATP receptor activation, eNOS is dissociated from caveolin-1 and in turn directly associates with TRPC5, which accumulates at the plasma membrane dependently on Ca2+ influx and calmodulin. This protein reassembly likely results in a relief of eNOS from the inhibitory action of caveolin-1 and an enhanced TRPC5 S-nitrosylation by eNOS localized in the proximity, thereby facilitating the secondary activation of Ca2+ influx and NO production. In isolated rat aorta, vasodilation induced by acetylcholine was significantly suppressed by the TRPC5 inhibitor AC1903. Thus, our study provides evidence that dynamic remodeling of the protein assemblies among TRPC5, eNOS, caveolin-1, and calmodulin determines the ensemble of Ca2+ mobilization and NO production in vascular endothelial cells.
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Affiliation(s)
- Reiko Sakaguchi
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan; Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan; Laboratory of Biomaterials and Chemistry, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
| | - Nobuaki Takahashi
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan; Advanced Biomedical Engineering Research Unit, Kyoto University, Kyoto, Japan
| | - Takashi Yoshida
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan; Division of Pharmacology, Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo, Japan
| | - Nozomi Ogawa
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Yoshifumi Ueda
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Satoshi Hamano
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Kaori Yamaguchi
- Laboratory of Environmental Systems Biology, Department of Technology and Ecology, Hall of Global Environmental Studies, Kyoto University, Kyoto, Japan
| | - Seishiro Sawamura
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Shinichiro Yamamoto
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan; Division of Pharmacology, Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo, Japan
| | - Yuji Hara
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan; Department of Integrative Physiology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Tomoya Kawamoto
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Ryosuke Suzuki
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Akito Nakao
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Masayuki X Mori
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan; Laboratory of Biomaterials and Chemistry, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
| | - Tetsushi Furukawa
- Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shunichi Shimizu
- Division of Pharmacology, Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo, Japan
| | - Ryuji Inoue
- Department of Physiology, Fukuoka University, Fukuoka, Japan
| | - Yasuo Mori
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan; Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan; Advanced Biomedical Engineering Research Unit, Kyoto University, Kyoto, Japan.
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7
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Tian W, Jia Q, Lin J, Luo J, He D, Yang J, Guo T, Guo H, Guo Y, Zhang W, Chen F, Ye Y, Liu J, Xu M, Deng C, Cui B, Su D, Wang H, Lu Y, Xiao J, Liu H, Yang J, Hou Z, Wang S. Remote neurostimulation through an endogenous ion channel using a near-infrared light-activatable nanoagonist. SCIENCE ADVANCES 2024; 10:eadn0367. [PMID: 39121219 PMCID: PMC11313869 DOI: 10.1126/sciadv.adn0367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 07/02/2024] [Indexed: 08/11/2024]
Abstract
The development of noninvasive approaches to precisely control neural activity in mammals is highly desirable. Here, we used the ion channel transient receptor potential ankyrin-repeat 1 (TRPA1) as a proof of principle, demonstrating remote near-infrared (NIR) activation of endogenous neuronal channels in mice through an engineered nanoagonist. This achievement enables specific neurostimulation in nongenetically modified mice. Initially, target-based screening identified flavins as photopharmacological agonists, allowing for the photoactivation of TRPA1 in sensory neurons upon ultraviolet A/blue light illumination. Subsequently, upconversion nanoparticles (UCNPs) were customized with an emission spectrum aligned to flavin absorption and conjugated with flavin adenine dinucleotide, creating a nanoagonist capable of NIR activation of TRPA1. Following the intrathecal injection of the nanoagonist, noninvasive NIR stimulation allows precise bidirectional control of nociception in mice through remote activation of spinal TRPA1. This study demonstrates a noninvasive NIR neurostimulation method with the potential for adaptation to various endogenous ion channels and neural processes by combining photochemical toolboxes with customized UCNPs.
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Affiliation(s)
- Weifeng Tian
- The Affiliated TCM Hospital of Guangzhou Medical University, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- Institute of Organoid Technology, Kunming Medical University, Kunming, China
- Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Qi Jia
- Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Jiewen Lin
- The Affiliated TCM Hospital of Guangzhou Medical University, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Jiamin Luo
- The Affiliated TCM Hospital of Guangzhou Medical University, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Dongmei He
- The Affiliated TCM Hospital of Guangzhou Medical University, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Jie Yang
- The Affiliated TCM Hospital of Guangzhou Medical University, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Tao Guo
- The Affiliated TCM Hospital of Guangzhou Medical University, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Huiling Guo
- The Affiliated TCM Hospital of Guangzhou Medical University, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Yusheng Guo
- GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, The Affiliated TCM Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, GMU-GIBH Joint School of Life Sciences, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University, Guangzhou, China
| | - Wenjie Zhang
- The Affiliated TCM Hospital of Guangzhou Medical University, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Feiyu Chen
- The Affiliated TCM Hospital of Guangzhou Medical University, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Ying Ye
- The Affiliated TCM Hospital of Guangzhou Medical University, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Jingjing Liu
- The Affiliated TCM Hospital of Guangzhou Medical University, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Mindong Xu
- The Affiliated TCM Hospital of Guangzhou Medical University, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Chengjie Deng
- Cell Biology and Molecular Biology Laboratory of Experimental Teaching Center, Faculty of Basic Medical Science, Kunming Medical University, Kunming, China
| | - Boxiang Cui
- The Affiliated TCM Hospital of Guangzhou Medical University, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Deyuan Su
- Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Hao Wang
- Department of Neurobiology and Department of Neurosurgery of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yi Lu
- Department of Anesthesiology, The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jianru Xiao
- Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Heng Liu
- GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, The Affiliated TCM Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, GMU-GIBH Joint School of Life Sciences, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University, Guangzhou, China
| | - Jian Yang
- Department of Biological Sciences, Columbia University, New York, NY 10027, USA
| | - Zhiyao Hou
- The Affiliated TCM Hospital of Guangzhou Medical University, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Shu Wang
- The Affiliated TCM Hospital of Guangzhou Medical University, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
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Fila M, Przyslo L, Derwich M, Sobczuk P, Pawlowska E, Blasiak J. The TRPA1 Ion Channel Mediates Oxidative Stress-Related Migraine Pathogenesis. Molecules 2024; 29:3385. [PMID: 39064963 PMCID: PMC11280075 DOI: 10.3390/molecules29143385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 07/12/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
Although the introduction of drugs targeting calcitonin gene-related peptide (CGRP) revolutionized migraine treatment, still a substantial proportion of migraine patients do not respond satisfactorily to such a treatment, and new therapeutic targets are needed. Therefore, molecular studies on migraine pathogenesis are justified. Oxidative stress is implicated in migraine pathogenesis, as many migraine triggers are related to the production of reactive oxygen and nitrogen species (RONS). Migraine has been proposed as a superior mechanism of the brain to face oxidative stress resulting from energetic imbalance. However, the precise mechanism behind the link between migraine and oxidative stress is not known. Nociceptive primary afferent nerve fiber endings express ion channel receptors that change harmful stimuli into electric pain signals. Transient receptor potential cation channel subfamily A member 1 (TRPA1) is an ion channel that can be activated by oxidative stress products and stimulate the release of CGRP from nerve endings. It is a transmembrane protein with ankyrin repeats and conserved cysteines in its N-terminus embedded in the cytosol. TRPA1 may be a central element of the signaling pathway from oxidative stress and NO production to CGRP release, which may play a critical role in headache induction. In this narrative review, we present information on the role of oxidative stress in migraine pathogenesis and provide arguments that TRPA1 may be "a missing link" between oxidative stress and migraine and therefore a druggable target in this disease.
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Affiliation(s)
- Michal Fila
- Department of Developmental Neurology and Epileptology, Polish Mother’s Memorial Hospital Research Institute, 93-338 Lodz, Poland; (M.F.); (L.P.)
| | - Lukasz Przyslo
- Department of Developmental Neurology and Epileptology, Polish Mother’s Memorial Hospital Research Institute, 93-338 Lodz, Poland; (M.F.); (L.P.)
| | - Marcin Derwich
- Department of Pediatric Dentistry, Medical University of Lodz, 92-217 Lodz, Poland; (M.D.); (E.P.)
| | - Piotr Sobczuk
- Emergency Medicine and Disaster Medicine Department, Medical University of Lodz, 92-209 Lodz, Poland;
- Department of Orthopaedics and Traumatology, Polish Mothers’ Memorial Hospital–Research Institute, Rzgowska 281, 93-338 Lodz, Poland
| | - Elzbieta Pawlowska
- Department of Pediatric Dentistry, Medical University of Lodz, 92-217 Lodz, Poland; (M.D.); (E.P.)
| | - Janusz Blasiak
- Faculty of Medicine, Collegium Medicum, Mazovian Academy in Plock, 09-402 Plock, Poland
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9
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Kimura H. Hydrogen Sulfide (H 2S)/Polysulfides (H 2S n) Signalling and TRPA1 Channels Modification on Sulfur Metabolism. Biomolecules 2024; 14:129. [PMID: 38275758 PMCID: PMC10813152 DOI: 10.3390/biom14010129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/11/2024] [Accepted: 01/17/2024] [Indexed: 01/27/2024] Open
Abstract
Hydrogen sulfide (H2S) and polysulfides (H2Sn, n ≥ 2) produced by enzymes play a role as signalling molecules regulating neurotransmission, vascular tone, cytoprotection, inflammation, oxygen sensing, and energy formation. H2Sn, which have additional sulfur atoms to H2S, and other S-sulfurated molecules such as cysteine persulfide and S-sulfurated cysteine residues of proteins, are produced by enzymes including 3-mercaptopyruvate sulfurtransferase (3MST). H2Sn are also generated by the chemical interaction of H2S with NO, or to a lesser extent with H2O2. S-sulfuration (S-sulfhydration) has been proposed as a mode of action of H2S and H2Sn to regulate the activity of target molecules. Recently, we found that H2S/H2S2 regulate the release of neurotransmitters, such as GABA, glutamate, and D-serine, a co-agonist of N-methyl-D-aspartate (NMDA) receptors. H2S facilitates the induction of hippocampal long-term potentiation, a synaptic model of memory formation, by enhancing the activity of NMDA receptors, while H2S2 achieves this by activating transient receptor potential ankyrin 1 (TRPA1) channels in astrocytes, potentially leading to the activation of nearby neurons. The recent findings show the other aspects of TRPA1 channels-that is, the regulation of the levels of sulfur-containing molecules and their metabolizing enzymes. Disturbance of the signalling by H2S/H2Sn has been demonstrated to be involved in various diseases, including cognitive and psychiatric diseases. The physiological and pathophysiological roles of these molecules will be discussed.
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Affiliation(s)
- Hideo Kimura
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, 1-1-1 Daigaku-Dori, Sanyo-Onoda 756-0884, Yamaguchi, Japan
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10
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Vlachova V, Barvik I, Zimova L. Human Transient Receptor Potential Ankyrin 1 Channel: Structure, Function, and Physiology. Subcell Biochem 2024; 104:207-244. [PMID: 38963489 DOI: 10.1007/978-3-031-58843-3_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/05/2024]
Abstract
The transient receptor potential ion channel TRPA1 is a Ca2+-permeable nonselective cation channel widely expressed in sensory neurons, but also in many nonneuronal tissues typically possessing barrier functions, such as the skin, joint synoviocytes, cornea, and the respiratory and intestinal tracts. Here, the primary role of TRPA1 is to detect potential danger stimuli that may threaten the tissue homeostasis and the health of the organism. The ability to directly recognize signals of different modalities, including chemical irritants, extreme temperatures, or osmotic changes resides in the characteristic properties of the ion channel protein complex. Recent advances in cryo-electron microscopy have provided an important framework for understanding the molecular basis of TRPA1 function and have suggested novel directions in the search for its pharmacological regulation. This chapter summarizes the current knowledge of human TRPA1 from a structural and functional perspective and discusses the complex allosteric mechanisms of activation and modulation that play important roles under physiological or pathophysiological conditions. In this context, major challenges for future research on TRPA1 are outlined.
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Affiliation(s)
- Viktorie Vlachova
- Department of Cellular Neurophysiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
| | - Ivan Barvik
- Division of Biomolecular Physics, Institute of Physics, Faculty of Mathematics and Physics, Charles University, Prague, Czech Republic.
| | - Lucie Zimova
- Department of Cellular Neurophysiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
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11
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Nakagawa T, Kaneko S. Role of TRPA1 in Painful Cold Hypersensitivity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1461:245-252. [PMID: 39289286 DOI: 10.1007/978-981-97-4584-5_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Transient receptor potential ankyrin 1 (TRPA1) is a polymodal cation channel that plays a pivotal role in pain generation after exposure to irritant chemicals and is involved in the sensation of a wide variety of pathological pain. TRPA1 was first reported to be sensitive to noxious cold, but its intrinsic cold sensitivity still remains under debate. To address this issue, we focused on cold hypersensitivity induced by oxaliplatin, a platinum-based chemotherapeutic drug, as a peculiar adverse symptom of acute peripheral neuropathy. We and other groups have shown that oxaliplatin enhances TRPA1 sensitivity to its chemical agonists and reactive oxygen species (ROS). Our in vitro and animal model studies revealed that oxaliplatin, or its metabolite oxalate, inhibits hydroxylation of a proline residue within the N-terminus of human TRPA1 (hTRPA1) via inhibition of prolyl hydroxylase domain-containing protein (PHD), which induces TRPA1 sensitization to ROS. Although hTRPA1 is insensitive to cold, PHD inhibition endows hTRPA1 with cold sensitivity through sensing the small amount of ROS produced after exposure to cold. Hence, we propose that PHD inhibition can unveil the cold sensitivity of hTRPA1 by converting ROS signaling into cold sensitivity. Furthermore, in this review, we summarize the role of TRPA1 in painful cold hypersensitivity during peripheral vascular impairment.
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Affiliation(s)
- Takayuki Nakagawa
- Department of Clinical Pharmacology and Pharmacotherapy, Wakayama Medical University, Wakayama, Japan.
| | - Shuji Kaneko
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
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12
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Nakao A, Liu K, Takahashi N, Mori Y. [Universal roles of the TRPA1 channel in oxygen-sensing]. Nihon Yakurigaku Zasshi 2024; 159:165-168. [PMID: 38692881 DOI: 10.1254/fpj.23086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2024]
Abstract
Molecular oxygen suffices the ATP production required for the survival of us aerobic organisms. But it is also true that oxygen acts as a source of reactive oxygen species that elicit a spectrum of damages in living organisms. To cope with such intrinsic ambiguity of biological activity oxygen exerts, aerobic mechanisms are equipped with an exquisite adaptive system, which sensitively detects partial pressure of oxygen within the body and controls appropriate oxygen supply to the tissues. Physiological responses to hypoxia are comprised of the acute and chronic phases, in the former of which the oxygen-sensing remains controversial particularly from mechanistic points of view. Recently, we have revealed that the prominently redox-sensitive cation channel TRPA1 plays key roles in oxygen-sensing mechanisms identified in the peripheral tissues and the central nervous system. In this review, we summarize recent development of researches on oxygen-sensing mechanisms including that in the carotid body, which has been recognized as the oxygen receptor organ central to acute oxygen-sensing. We also discuss how ubiquitously the TRPA1 contributes to the mechanisms underlying the acute phase of adaptation to hypoxia.
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Affiliation(s)
- Akito Nakao
- Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University
| | - Ke Liu
- Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University
| | - Nobuaki Takahashi
- Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University
| | - Yasuo Mori
- Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University
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13
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Fan YG, Wu TY, Zhao LX, Jia RJ, Ren H, Hou WJ, Wang ZY. From zinc homeostasis to disease progression: Unveiling the neurodegenerative puzzle. Pharmacol Res 2024; 199:107039. [PMID: 38123108 DOI: 10.1016/j.phrs.2023.107039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/16/2023] [Accepted: 12/10/2023] [Indexed: 12/23/2023]
Abstract
Zinc is a crucial trace element in the human body, playing a role in various physiological processes such as oxidative stress, neurotransmission, protein synthesis, and DNA repair. The zinc transporters (ZnTs) family members are responsible for exporting intracellular zinc, while Zrt- and Irt-like proteins (ZIPs) are involved in importing extracellular zinc. These processes are essential for maintaining cellular zinc homeostasis. Imbalances in zinc metabolism have been linked to the development of neurodegenerative diseases. Disruptions in zinc levels can impact the survival and activity of neurons, thereby contributing to the progression of neurodegenerative diseases through mechanisms like cell apoptosis regulation, protein phase separation, ferroptosis, oxidative stress, and neuroinflammation. Therefore, conducting a systematic review of the regulatory network of zinc and investigating the relationship between zinc dysmetabolism and neurodegenerative diseases can enhance our understanding of the pathogenesis of these diseases. Additionally, it may offer new insights and approaches for the treatment of neurodegenerative diseases.
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Affiliation(s)
- Yong-Gang Fan
- Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang 110122, China.
| | - Ting-Yao Wu
- First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121000, China
| | - Ling-Xiao Zhao
- Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang 110122, China
| | - Rong-Jun Jia
- Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang 110122, China
| | - Hang Ren
- Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang 110122, China
| | - Wen-Jia Hou
- Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang 110122, China
| | - Zhan-You Wang
- Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang 110122, China.
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14
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Imamura T, Ogawa T, Minagawa T, Daimon H, Nagai T, Ueno M, Saito T, Ishizuka O. Transient receptor potential ankyrin 1 channels in the bladder mediate low temperature elicited bladder overactivity in rats. Neurourol Urodyn 2024; 43:276-288. [PMID: 38010891 DOI: 10.1002/nau.25335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 10/13/2023] [Accepted: 11/08/2023] [Indexed: 11/29/2023]
Abstract
AIMS This study aimed to investigate whether pathways involving transient receptor potential ankyrin 1 (TRPA1) channels in the urinary bladder mediate the bladder overactivity elicited by exposure to a low temperature in rats. METHODS At postnatal week 10, female Sprague-Dawley (SD) rats were intraperitoneally injected with the TRPA1 channel antagonist, HC030031, at room temperature (RT) and subsequently exposed to low temperature (LT). Bladder specimens treated with HC030031 were evaluated for contractions through cumulative addition of the TRPA1 channel agonist trans-cinnamaldehyde. Two days before cystometric investigation, small interfering RNA (siRNA) targeting TRPA1 was transfected into urinary bladders. Then, cystometric investigations were performed on rats subjected to TRPA1 siRNA transfection at both RT and LT. Expression of TRPA1 channels in the urinary bladder was assessed through immunohistochemistry and real-time reverse transcription-polymerase chain reaction. RESULTS At RT, micturition patterns were unaffected by HC030031 treatment. However, upon exposure to LT, rats treated with HC030031 exhibited a reduction of LT-elicited bladder overactivity, as evidenced by inhibited decreases in voiding interval, micturition volume, and bladder capacity. Additionally, HC030031 inhibited trans-cinnamaldehyde-induced contractions. Immunohistochemical analysis showed the presence of TRPA1 channels in the urinary bladder. Notably, rats with TRPA1 siRNA-transfected bladders could partially inhibit bladder overactivity during LT exposure. CONCLUSIONS These findings indicate that pathways involving TRPA1 channels expressed in the urinary bladder could mediate the LT-elicited bladder overactivity.
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Affiliation(s)
- Tetsuya Imamura
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Teruyuki Ogawa
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Tomonori Minagawa
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Hironori Daimon
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Takashi Nagai
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Manabu Ueno
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Tetsuichi Saito
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Osamu Ishizuka
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
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15
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Ye P, Fang Q, Hu X, Zou W, Huang M, Ke M, Li Y, Liu M, Cai X, Zhang C, Hua N, Al-Sheikh U, Liu X, Yu P, Jiang P, Pan PY, Luo J, Jiang LH, Xu S, Fang EF, Su H, Kang L, Yang W. TRPM2 as a conserved gatekeeper determines the vulnerability of DA neurons by mediating ROS sensing and calcium dyshomeostasis. Prog Neurobiol 2023; 231:102530. [PMID: 37739206 DOI: 10.1016/j.pneurobio.2023.102530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 09/01/2023] [Accepted: 09/17/2023] [Indexed: 09/24/2023]
Abstract
Different dopaminergic (DA) neuronal subgroups exhibit distinct vulnerability to stress, while the underlying mechanisms are elusive. Here we report that the transient receptor potential melastatin 2 (TRPM2) channel is preferentially expressed in vulnerable DA neuronal subgroups, which correlates positively with aging in Parkinson's Disease (PD) patients. Overexpression of human TRPM2 in the DA neurons of C. elegans resulted in selective death of ADE but not CEP neurons in aged worms. Mechanistically, TRPM2 activation mediates FZO-1/CED-9-dependent mitochondrial hyperfusion and mitochondrial permeability transition (MPT), leading to ADE death. In mice, TRPM2 knockout reduced vulnerable substantia nigra pars compacta (SNc) DA neuronal death induced by stress. Moreover, the TRPM2-mediated vulnerable DA neuronal death pathway is conserved from C. elegans to toxin-treated mice model and PD patient iPSC-derived DA neurons. The vulnerable SNc DA neuronal loss is the major symptom and cause of PD, and therefore the TRPM2-mediated pathway serves as a promising therapeutic target against PD.
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Affiliation(s)
- Peiwu Ye
- Department of Biophysics, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Qiuyuan Fang
- Department of Biophysics, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Xupang Hu
- Second Clinical Medical College, Affiliated Secondary Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310011, China
| | - Wenjuan Zou
- Department of Neurobiology and Department of Neurosurgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang 310053, China
| | - Miaodan Huang
- Institute of Chinese Medical Sciences, University of Macau, Macau, China
| | - Minjing Ke
- Institute of Chinese Medical Sciences, University of Macau, Macau, China
| | - Yunhao Li
- Institute of Chinese Medical Sciences, University of Macau, Macau, China
| | - Min Liu
- Department of Biophysics, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Xiaobo Cai
- Department of Biophysics, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Congyi Zhang
- Department of Biophysics, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Ning Hua
- Department of Biophysics, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Umar Al-Sheikh
- Department of Neurobiology and Department of Neurosurgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang 310053, China
| | - Xingyu Liu
- Department of Biophysics, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Peilin Yu
- Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Peiran Jiang
- School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China
| | - Ping-Yue Pan
- Department of Neuroscience and Cell Biology, Rutgers University Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA
| | - Jianhong Luo
- School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China
| | - Lin-Hua Jiang
- School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK; Sino-UK Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Neurobiology, Xinxiang Medical University, Xinxiang 453000, China; University of Leeds, Leeds LS2 9JT, UK
| | - Suhong Xu
- Center for Stem Cell and Regenerative Medicine and Department of Cardiology of The Second Affiliated Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China
| | - Evandro F Fang
- Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway
| | - Huanxing Su
- Institute of Chinese Medical Sciences, University of Macau, Macau, China.
| | - Lijun Kang
- Second Clinical Medical College, Affiliated Secondary Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310011, China; School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China.
| | - Wei Yang
- Department of Biophysics, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
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Li C, Xu J, Abdurehim A, Sun Q, Xie J, Zhang Y. TRPA1: A promising target for pulmonary fibrosis? Eur J Pharmacol 2023; 959:176088. [PMID: 37777106 DOI: 10.1016/j.ejphar.2023.176088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 09/20/2023] [Accepted: 09/26/2023] [Indexed: 10/02/2023]
Abstract
Pulmonary fibrosis is a disease characterized by progressive scar formation and the ultimate manifestation of numerous lung diseases. It is known as "cancer that is not cancer" and has attracted widespread attention. However, its formation process is very complex, and the mechanism of occurrence has not been fully elucidated. Current research has found that TRPA1 may be a promising target in the pathogenesis of pulmonary fibrosis. The TRPA1 channel was first successfully isolated in human lung fibroblasts, and it was found to have a relatively concentrated distribution in the lungs and respiratory tract. It is also involved in various acute and chronic inflammatory processes of lung diseases and may even play a core role in the progression and/or prevention of pulmonary fibrosis. Natural ligands targeting TRPA1 could offer a promising alternative treatment for pulmonary diseases. Therefore, this review delves into the current understanding of pulmonary fibrogenesis, analyzes TRPA1 biological properties and regulation of lung disease with a focus on pulmonary fibrosis, summarizes the TRPA1 molecular structure and its biological function, and summarizes TRPA1 natural ligand sources, anti-pulmonary fibrosis activity and potential mechanisms. The aim is to decipher the exact role of TRPA1 channels in the pathophysiology of pulmonary fibrosis and to consider their potential in the development of new therapeutic strategies.
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Affiliation(s)
- Chao Li
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
| | - Jiawen Xu
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
| | - Aliya Abdurehim
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
| | - Qing Sun
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
| | - Junbo Xie
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
| | - Yanqing Zhang
- Biotechnology & Food Science College, Tianjin University of Commerce, Tianjin, 300134, China.
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York JM. Temperature activated transient receptor potential ion channels from Antarctic fishes. Open Biol 2023; 13:230215. [PMID: 37848053 PMCID: PMC10581778 DOI: 10.1098/rsob.230215] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 09/01/2023] [Indexed: 10/19/2023] Open
Abstract
Antarctic notothenioid fishes (cryonotothenioids) live in waters that range between -1.86°C and an extreme maximum +4°C. Evidence suggests these fish sense temperature peripherally, but the molecular mechanism of temperature sensation in unknown. Previous work identified transient receptor potential (TRP) channels TRPA1b, TRPM4 and TRPV1a as the top candidates for temperature sensors. Here, cryonotothenioid TRPA1b and TRPV1a are characterized using Xenopus oocyte electrophysiology. TRPA1b and TRPV1a showed heat-evoked currents with Q10s of 11.1 ± 2.2 and 20.5 ± 2.4, respectively. Unexpectedly, heat activation occurred at a threshold of 22.9 ± 1.3°C for TRPA1b and 32.1 ± 0.6°C for TRPV1a. These fish have not experienced such temperatures for at least 15 Myr. Either (1) another molecular mechanism underlies temperature sensation, (2) these fishes do not sense temperatures below these thresholds despite having lethal limits as low as 5°C, or (3) native cellular conditions modify the TRP channels to function at relevant temperatures. The effects of osmolytes, pH, oxidation, phosphorylation, lipids and accessory proteins were tested. No conditions shifted the activity range of TRPV1a. Oxidation in combination with reduced cholesterol significantly dropped activation threshold of TRPA1b to 11.3 ± 2.3°C, it is hypothesized the effect may be due to lipid raft disruption.
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Affiliation(s)
- Julia M. York
- Department of Integrative Biology, Institute for Neuroscience, University of Texas at Austin, Austin, TX, USA
- School of Integrative Biology, University of Illinois Urbana–Champaign, Urbana, Illinois, USA
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Kakae M, Nakajima H, Tobori S, Kawashita A, Miyanohara J, Morishima M, Nagayasu K, Nakagawa T, Shigetomi E, Koizumi S, Mori Y, Kaneko S, Shirakawa H. The astrocytic TRPA1 channel mediates an intrinsic protective response to vascular cognitive impairment via LIF production. SCIENCE ADVANCES 2023; 9:eadh0102. [PMID: 37478173 PMCID: PMC10361588 DOI: 10.1126/sciadv.adh0102] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 06/20/2023] [Indexed: 07/23/2023]
Abstract
Vascular cognitive impairment (VCI) refers to cognitive alterations caused by vascular disease, which is associated with various types of dementia. Because chronic cerebral hypoperfusion (CCH) induces VCI, we used bilateral common carotid artery stenosis (BCAS) mice as a CCH-induced VCI model. Transient receptor potential ankyrin 1 (TRPA1), the most redox-sensitive TRP channel, is functionally expressed in the brain. Here, we investigated the pathophysiological role of TRPA1 in CCH-induced VCI. During early-stage CCH, cognitive impairment and white matter injury were induced by BCAS in TRPA1-knockout but not wild-type mice. TRPA1 stimulation with cinnamaldehyde ameliorated BCAS-induced outcomes. RNA sequencing analysis revealed that BCAS increased leukemia inhibitory factor (LIF) in astrocytes. Moreover, hydrogen peroxide-treated TRPA1-stimulated primary astrocyte cultures expressed LIF, and culture medium derived from these cells promoted oligodendrocyte precursor cell myelination. Overall, TRPA1 in astrocytes prevents CCH-induced VCI through LIF production. Therefore, TRPA1 stimulation may be a promising therapeutic approach for VCI.
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Affiliation(s)
- Masashi Kakae
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
- Department of Clinical Pharmacology and Pharmacotherapy, School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama, Japan
| | - Hiroki Nakajima
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Shota Tobori
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Ayaka Kawashita
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Jun Miyanohara
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Misa Morishima
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Kazuki Nagayasu
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Takayuki Nakagawa
- Department of Clinical Pharmacology and Pharmacotherapy, School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama, Japan
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan
| | - Eiji Shigetomi
- Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan
- Yamanashi GLIA Center, University of Yamanashi, Yamanashi, Japan
| | - Schuichi Koizumi
- Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan
- Yamanashi GLIA Center, University of Yamanashi, Yamanashi, Japan
| | - Yasuo Mori
- Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Shuji Kaneko
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Hisashi Shirakawa
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
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19
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Giacco V, Flower G, Artamonova M, Hunter J, Padilla Requerey A, Hamilton NB. Transient receptor potential Ankyrin-1 (TRPA1) agonists suppress myelination and induce demyelination in organotypic cortical slices. Glia 2023; 71:1402-1413. [PMID: 36762504 PMCID: PMC10953362 DOI: 10.1002/glia.24347] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 01/16/2023] [Accepted: 01/17/2023] [Indexed: 02/11/2023]
Abstract
Oligodendrocytes are highly specialized glial cells characterized by their production of multilayer myelin sheaths that wrap axons to speed up action potential propagation. It is due to their specific role in supporting axons that impairment of myelin structure and function leads to debilitating symptoms in a wide range of degenerative diseases, including Multiple Sclerosis and Leukodystrophies. It is known that myelin damage can be receptor-mediated and recently oligodendrocytes have been shown to express Ca2+ -permeable Transient Receptor Potential Ankyrin-1 (TRPA1) channels, whose activation can result in myelin damage in ischemia. Here, we show, using organotypic cortical slice cultures, that TRPA1 activation, by TRPA1 agonists JT010 and Carvacrol for varying lengths of time, induces myelin damage. Although TRPA1 activation does not appear to affect oligodendrocyte progenitor cell number or proliferation, it prevents myelin formation and after myelination causes internodal shrinking and significant myelin degradation. This does not occur when the TRPA1 antagonist, A967079, is also applied. Of note is that when TRPA1 agonists are applied for either 24 h, 3 days or 7 days, axon integrity appears to be preserved while mature myelinated oligodendrocytes remain but with significantly shortened internodes. These results provide further evidence that TRPA1 inhibition could be protective in demyelination diseases and a promising therapy to prevent demyelination and promote remyelination.
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Affiliation(s)
- Vincenzo Giacco
- Wolfson Centre for Age‐Related DiseasesInstitute of Psychiatry, Psychology and Neuroscience, Guy's Campus, King's College LondonLondonUK
| | - Grace Flower
- Wolfson Centre for Age‐Related DiseasesInstitute of Psychiatry, Psychology and Neuroscience, Guy's Campus, King's College LondonLondonUK
| | - Maria Artamonova
- Wolfson Centre for Age‐Related DiseasesInstitute of Psychiatry, Psychology and Neuroscience, Guy's Campus, King's College LondonLondonUK
| | - Jake Hunter
- Wolfson Centre for Age‐Related DiseasesInstitute of Psychiatry, Psychology and Neuroscience, Guy's Campus, King's College LondonLondonUK
| | - Aitana Padilla Requerey
- Wolfson Centre for Age‐Related DiseasesInstitute of Psychiatry, Psychology and Neuroscience, Guy's Campus, King's College LondonLondonUK
| | - Nicola B. Hamilton
- Wolfson Centre for Age‐Related DiseasesInstitute of Psychiatry, Psychology and Neuroscience, Guy's Campus, King's College LondonLondonUK
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20
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Moccia F, Montagna D. Transient Receptor Potential Ankyrin 1 (TRPA1) Channel as a Sensor of Oxidative Stress in Cancer Cells. Cells 2023; 12:cells12091261. [PMID: 37174661 PMCID: PMC10177399 DOI: 10.3390/cells12091261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/20/2023] [Accepted: 04/20/2023] [Indexed: 05/15/2023] Open
Abstract
Moderate levels of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), fuel tumor metastasis and invasion in a variety of cancer types. Conversely, excessive ROS levels can impair tumor growth and metastasis by triggering cancer cell death. In order to cope with the oxidative stress imposed by the tumor microenvironment, malignant cells exploit a sophisticated network of antioxidant defense mechanisms. Targeting the antioxidant capacity of cancer cells or enhancing their sensitivity to ROS-dependent cell death represent a promising strategy for alternative anticancer treatments. Transient Receptor Potential Ankyrin 1 (TRPA1) is a redox-sensitive non-selective cation channel that mediates extracellular Ca2+ entry upon an increase in intracellular ROS levels. The ensuing increase in intracellular Ca2+ concentration can in turn engage a non-canonical antioxidant defense program or induce mitochondrial Ca2+ dysfunction and apoptotic cell death depending on the cancer type. Herein, we sought to describe the opposing effects of ROS-dependent TRPA1 activation on cancer cell fate and propose the pharmacological manipulation of TRPA1 as an alternative therapeutic strategy to enhance cancer cell sensitivity to oxidative stress.
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Affiliation(s)
- Francesco Moccia
- Laboratory of General Physiology, Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, 27100 Pavia, Italy
| | - Daniela Montagna
- Department of Sciences Clinic-Surgical, Diagnostic and Pediatric, University of Pavia, 27100 Pavia, Italy
- Pediatric Clinic, Foundation IRCCS Policlinico San Matteo, 27100 Pavia, Italy
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21
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The Impact of Plasma Membrane Ion Channels on Bone Remodeling in Response to Mechanical Stress, Oxidative Imbalance, and Acidosis. Antioxidants (Basel) 2023; 12:antiox12030689. [PMID: 36978936 PMCID: PMC10045377 DOI: 10.3390/antiox12030689] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/01/2023] [Accepted: 03/03/2023] [Indexed: 03/14/2023] Open
Abstract
The extracellular milieu is a rich source of different stimuli and stressors. Some of them depend on the chemical–physical features of the matrix, while others may come from the ‘outer’ environment, as in the case of mechanical loading applied on the bones. In addition to these forces, a plethora of chemical signals drives cell physiology and fate, possibly leading to dysfunctions when the homeostasis is disrupted. This variety of stimuli triggers different responses among the tissues: bones represent a particular milieu in which a fragile balance between mechanical and metabolic demands should be tuned and maintained by the concerted activity of cell biomolecules located at the interface between external and internal environments. Plasma membrane ion channels can be viewed as multifunctional protein machines that act as rapid and selective dual-nature hubs, sensors, and transducers. Here we focus on some multisensory ion channels (belonging to Piezo, TRP, ASIC/EnaC, P2XR, Connexin, and Pannexin families) actually or potentially playing a significant role in bone adaptation to three main stressors, mechanical forces, oxidative stress, and acidosis, through their effects on bone cells including mesenchymal stem cells, osteoblasts, osteoclasts, and osteocytes. Ion channel-mediated bone remodeling occurs in physiological processes, aging, and human diseases such as osteoporosis, cancer, and traumatic events.
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22
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Kawabata R, Shimoyama S, Ueno S, Yao I, Arata A, Koga K. TRPA1 as a O 2 sensor detects microenvironmental hypoxia in the mice anterior cingulate cortex. Sci Rep 2023; 13:2960. [PMID: 36807332 PMCID: PMC9941080 DOI: 10.1038/s41598-023-29140-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 01/31/2023] [Indexed: 02/22/2023] Open
Abstract
Transient receptor potential ankyrin 1 (TRPA1) is a member of the TRP channel family and is expressed in peripheral and central nervous systems. In the periphery, TRPA1 senses cold and pain. However, the functions of TRPA1 in the CNS are unclear. Here, we examined the roles of TRPA1 on neural activity and synaptic transmission in layer II/III pyramidal neurons from mice anterior cingulate cortex (ACC) by whole-cell patch-clamp recordings. The activation of Cinnamaldehyde (CA), which is TRPA1 agonist produced inward currents and these were blocked by the TRPA1 antagonists. Furthermore, activating TRPA1 changed the properties of action potentials such as the firing rate, rise time and decay time. In contrast, stimulating TRPA1 did not alter the spontaneous synaptic transmission. Finally, we examined the functional role of TRPA1 on neurons in a hypoxic environment. We induced an acute hypoxia by substituting nitrogen (N2) gas for oxygen (O2) in the external solution. N2 produced biphasic effects that consisting of inward currents in the early phase and outward currents in the late phase. Importantly, blocking TRPA1 reduced inward currents, but not outward currents. In contrast, a KATP channel blocker completely inhibited outward currents. These results suggest that TRPA1 acts on postsynaptic neurons in the ACC as an acute O2 sensor.
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Affiliation(s)
- Ryo Kawabata
- grid.258777.80000 0001 2295 9421Department of Biomedical Chemistry major, Graduate School of Science and Technology, Kwansei Gakuin University, Sanda, Hyogo Japan ,grid.272264.70000 0000 9142 153XDepartment of Neurophysiology, Hyogo Medical University, Nishinomiya, Hyogo Japan
| | - Shuji Shimoyama
- grid.257016.70000 0001 0673 6172Department of Neurophysiology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori Japan
| | - Shinya Ueno
- grid.257016.70000 0001 0673 6172Department of Neurophysiology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori Japan
| | - Ikuko Yao
- grid.258777.80000 0001 2295 9421Department of Biomedical Chemistry major, Graduate School of Science and Technology, Kwansei Gakuin University, Sanda, Hyogo Japan
| | - Akiko Arata
- Department of Physiology, Hyogo Medical University, Nishinomiya, Hyogo, Japan.
| | - Kohei Koga
- Department of Neurophysiology, Hyogo Medical University, Nishinomiya, Hyogo, Japan.
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23
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Saward BG, Leissing TM, Clifton IJ, Tumber A, Timperley CM, Hopkinson RJ, Schofield CJ. Biochemical and Structural Insights into FIH-Catalysed Hydroxylation of Transient Receptor Potential Ankyrin Repeat Domains. Chembiochem 2023; 24:e202200576. [PMID: 36448355 PMCID: PMC10946520 DOI: 10.1002/cbic.202200576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/28/2022] [Accepted: 11/28/2022] [Indexed: 12/03/2022]
Abstract
Transient receptor potential (TRP) channels have important roles in environmental sensing in animals. Human TRP subfamily A member 1 (TRPA1) is responsible for sensing allyl isothiocyanate (AITC) and other electrophilic sensory irritants. TRP subfamily vanilloid member 3 (TRPV3) is involved in skin maintenance. TRPV3 is a reported substrate of the 2-oxoglutarate oxygenase factor inhibiting hypoxia-inducible factor (FIH). We report biochemical and structural studies concerning asparaginyl hydroxylation of the ankyrin repeat domains (ARDs) of TRPA1 and TRPV3 catalysed by FIH. The results with ARD peptides support a previous report on FIH-catalysed TRPV3 hydroxylation and show that, of the 12 potential TRPA1 sequences investigated, one sequence (TRPA1 residues 322-348) undergoes hydroxylation at Asn336. Structural studies reveal that the TRPA1 and TRPV3 ARDs bind to FIH with a similar overall geometry to most other reported FIH substrates. However, the binding mode of TRPV3 to FIH is distinct from that of other substrates.
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Affiliation(s)
- Benjamin G. Saward
- Department of Chemistry and theIneos Oxford Institute for Antimicrobial ResearchChemistry Research LaboratoryMansfield RoadUniversity of OxfordOxfordOX1 3TAUK
| | - Thomas M. Leissing
- Department of Chemistry and theIneos Oxford Institute for Antimicrobial ResearchChemistry Research LaboratoryMansfield RoadUniversity of OxfordOxfordOX1 3TAUK
| | - Ian J. Clifton
- Department of Chemistry and theIneos Oxford Institute for Antimicrobial ResearchChemistry Research LaboratoryMansfield RoadUniversity of OxfordOxfordOX1 3TAUK
| | - Anthony Tumber
- Department of Chemistry and theIneos Oxford Institute for Antimicrobial ResearchChemistry Research LaboratoryMansfield RoadUniversity of OxfordOxfordOX1 3TAUK
| | | | - Richard J. Hopkinson
- Department of Chemistry and theIneos Oxford Institute for Antimicrobial ResearchChemistry Research LaboratoryMansfield RoadUniversity of OxfordOxfordOX1 3TAUK
- Present address: Leicester Institute for Structural and Chemical Biology and School of ChemistryUniversity of LeicesterHenry Wellcome Building, Lancaster RoadLeicesterLE1 7RHUK
| | - Christopher J. Schofield
- Department of Chemistry and theIneos Oxford Institute for Antimicrobial ResearchChemistry Research LaboratoryMansfield RoadUniversity of OxfordOxfordOX1 3TAUK
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24
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TRPA1 as Target in Myocardial Infarction. Int J Mol Sci 2023; 24:ijms24032516. [PMID: 36768836 PMCID: PMC9917254 DOI: 10.3390/ijms24032516] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/13/2023] [Accepted: 01/23/2023] [Indexed: 01/31/2023] Open
Abstract
Transient receptor potential cation channel subfamily A member 1 (TRPA1), an ion channel primarily expressed on sensory neurons, can be activated by substances occurring during myocardial infarction. Aims were to investigate whether activation, inhibition, or absence of TRPA1 affects infarcts and to explore underlying mechanisms. In the context of myocardial infarction, rats received a TRPA1 agonist, an antagonist, or vehicle at different time points, and infarct size was assessed. Wild type and TRPA1 knockout mice were also compared in this regard. In vitro, sensory neurons were co-cultured with cardiomyocytes and subjected to a model of ischemia-reperfusion. Although there was a difference between TRPA1 activation or inhibition in vivo, no experimental group was different to control animals in infarct size, which also applies to animals lacking TRPA1. In vitro, survival probability of cardiomyocytes challenged by ischemia-reperfusion increased from 32.8% in absence to 45.1% in presence of sensory neurons, which depends, at least partly, on TRPA1. This study raises doubts about whether TRPA1 is a promising target to reduce myocardial damage within a 24 h period. The results are incompatible with relevant enlargements of infarcts by TRPA1 activation or inhibition, which argues against adverse effects when TRPA1 is targeted for other indications.
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25
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Effect of cisplatin on oral ulcer-induced nociception in rats. Arch Oral Biol 2022; 144:105572. [DOI: 10.1016/j.archoralbio.2022.105572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 09/29/2022] [Accepted: 10/12/2022] [Indexed: 11/19/2022]
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26
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Zhang H, Wang C, Zhang K, Kamau PM, Luo A, Tian L, Lai R. The role of TRPA1 channels in thermosensation. CELL INSIGHT 2022; 1:100059. [PMID: 37193355 PMCID: PMC10120293 DOI: 10.1016/j.cellin.2022.100059] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 10/05/2022] [Accepted: 10/05/2022] [Indexed: 05/18/2023]
Abstract
Transient receptor potential ankyrin 1 (TRPA1) is a polymodal nonselective cation channel sensitive to different physical and chemical stimuli. TRPA1 is associated with many important physiological functions in different species and thus is involved in different degrees of evolution. TRPA1 acts as a polymodal receptor for the perceiving of irritating chemicals, cold, heat, and mechanical sensations in various animal species. Numerous studies have supported many functions of TRPA1, but its temperature-sensing function remains controversial. Although TRPA1 is widely distributed in both invertebrates and vertebrates, and plays a crucial role in tempreture sensing, the role of TRPA1 thermosensation and molecular temperature sensitivity are species-specific. In this review, we summarize the temperature-sensing role of TRPA1 orthologues in terms of molecular, cellular, and behavioural levels.
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Affiliation(s)
- Hao Zhang
- Key Laboratory of Animal Models and Human Disease Mechanisms, Key Laboratory of Bioactive Peptides of Yunnan Province, Engineering Laboratory of Bioactive Peptides, National & Local Joint Engineering Center of Natural Bioactive Peptides, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Kunming Primate Research Center, and National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650107, Yunnan, China
| | - Chengsan Wang
- Key Laboratory of Animal Models and Human Disease Mechanisms, Key Laboratory of Bioactive Peptides of Yunnan Province, Engineering Laboratory of Bioactive Peptides, National & Local Joint Engineering Center of Natural Bioactive Peptides, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Kunming Primate Research Center, and National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650107, Yunnan, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Keyi Zhang
- University of Chinese Academy of Sciences, Beijing, 100049, China
- School of Molecular Medicine, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310000, China
| | - Peter Muiruri Kamau
- Key Laboratory of Animal Models and Human Disease Mechanisms, Key Laboratory of Bioactive Peptides of Yunnan Province, Engineering Laboratory of Bioactive Peptides, National & Local Joint Engineering Center of Natural Bioactive Peptides, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Kunming Primate Research Center, and National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650107, Yunnan, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Sino-African Joint Research Center, Kunming Institute of Zoology, Chinese, Academy of Sciences, Kunming, Yunnan, 650223, China
| | - Anna Luo
- Key Laboratory of Animal Models and Human Disease Mechanisms, Key Laboratory of Bioactive Peptides of Yunnan Province, Engineering Laboratory of Bioactive Peptides, National & Local Joint Engineering Center of Natural Bioactive Peptides, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Kunming Primate Research Center, and National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650107, Yunnan, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Lifeng Tian
- University of Chinese Academy of Sciences, Beijing, 100049, China
- School of Molecular Medicine, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310000, China
| | - Ren Lai
- Key Laboratory of Animal Models and Human Disease Mechanisms, Key Laboratory of Bioactive Peptides of Yunnan Province, Engineering Laboratory of Bioactive Peptides, National & Local Joint Engineering Center of Natural Bioactive Peptides, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Kunming Primate Research Center, and National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650107, Yunnan, China
- Sino-African Joint Research Center, Kunming Institute of Zoology, Chinese, Academy of Sciences, Kunming, Yunnan, 650223, China
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27
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Valek L, Tran BN, Tegeder I. Cold avoidance and heat pain hypersensitivity in neuronal nucleoredoxin knockout mice. Free Radic Biol Med 2022; 192:84-97. [PMID: 36126861 DOI: 10.1016/j.freeradbiomed.2022.09.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 08/15/2022] [Accepted: 09/13/2022] [Indexed: 11/29/2022]
Abstract
Nucleoredoxin is a thioredoxin-like oxidoreductase that mainly acts as oxidase and thereby regulates calcium calmodulin kinase Camk2a, an effector of nitric oxide mediated synaptic potentiation and nociceptive sensitization. We asked here if and how NXN affects thermal sensation and nociception in mice using pan-neuronal NXN deletion driven by Nestin-Cre, and sensory neuron specific deletion driven by Advillin-Cre. In a thermal gradient ring, where mice can freely choose the temperature of well-being, Nestin-NXN-/- mice avoided unpleasant cold temperatures. In neuropathic and inflammatory nociceptive models, Nestin-NXN-/- and Advillin-NXN-/- mice displayed subtle phenotypes of heightened heat nociception. Abnormal thermal in vivo responses were associated with heightened calcium influx upon stimulation of transient receptor channels, with heightened oxygen consumption upon disruption of the mitochondrial membrane potential and with higher density of neurite trees of primary sensory neurons of the dorsal root ganglia in cultures. The data suggest that loss of NXN's balancing redox functions leads to maladaptive changes in sensory neurons that manifest in vivo as polyneuropathy-like abnormal cold sensitivity and heat "pain".
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Affiliation(s)
- Lucie Valek
- Institute of Clinical Pharmacology, Goethe-University, Faculty of Medicine, Frankfurt, Germany
| | - Bao Ngoc Tran
- Institute of Clinical Pharmacology, Goethe-University, Faculty of Medicine, Frankfurt, Germany
| | - Irmgard Tegeder
- Institute of Clinical Pharmacology, Goethe-University, Faculty of Medicine, Frankfurt, Germany.
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28
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Kida T, Takahashi N, Mori MX, Sun JH, Oota H, Nishino K, Okauchi T, Ochi Y, Kano D, Tateishi U, Watanabe Y, Cui Y, Mori Y, Doi H. N-Methylamide-structured SB366791 derivatives with high TRPV1 antagonistic activity: toward PET radiotracers to visualize TRPV1. RSC Med Chem 2022; 13:1197-1204. [PMID: 36325399 PMCID: PMC9579943 DOI: 10.1039/d2md00158f] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 08/27/2022] [Indexed: 09/08/2023] Open
Abstract
Transient receptor potential cation channel subfamily V member 1 (TRPV1)-targeted compounds were synthesized by modifying the structure of SB366791, a pharmaceutically representative TRPV1 antagonist. To avoid amide-iminol tautomerization, structurally supported N-methylated amides (i.e., 3-alkoxy-substitued N-meythylamide derivatives of SB366791) were evaluated using a Ca2+ influx assay, in which cells expressed recombinant TRPV1 in the presence of 1.0 μM capsaicin. The antagonistic activities of N-(3-methoxyphenyl)-N-methyl-4-chlorocinnamamide (2) (RLC-TV1004) and N-{3-(3-fluoropropoxy)phenyl}-N-methyl-4-chlorocinnamamide (4) (RLC-TV1006) were found to be approximately three-fold higher (IC50: 1.3 μM and 1.1 μM, respectively) than that of SB366791 (IC50: 3.7 μM). These results will help reinvigorate the potential of SB366791 in medicinal chemistry applications. The 3-methoxy and 3-fluoroalkoxy substituents were used to obtain radioactive [11C]methoxy- or [18F]fluoroalkoxy-incorporated tracers for in vivo positron emission tomography (PET). Using the 11C- or 18F-labeled derivatives, explorative PET imaging trials were performed in rats.
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Affiliation(s)
- Tatsuya Kida
- Laboratory for Labeling Chemistry, RIKEN Center for Biosystems Dynamics Research 6-7-3 Minatojima-minamimachi, Chuo-ku Kobe Hyogo 650-0047 Japan
| | - Nobuaki Takahashi
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University Nishikyo-ku Kyoto 615-8510 Japan
| | - Masayuki X Mori
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University Nishikyo-ku Kyoto 615-8510 Japan
| | - Jiacheng H Sun
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University Nishikyo-ku Kyoto 615-8510 Japan
| | - Hideto Oota
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University Nishikyo-ku Kyoto 615-8510 Japan
| | - Kosuke Nishino
- Laboratory for Labeling Chemistry, RIKEN Center for Biosystems Dynamics Research 6-7-3 Minatojima-minamimachi, Chuo-ku Kobe Hyogo 650-0047 Japan
| | - Takashi Okauchi
- Laboratory for Biofunction Dynamics Imaging, RIKEN Center for Biosystems Dynamics Research 6-7-3 Minatojima-minamimachi, Chuo-ku Kobe Hyogo 650-0047 Japan
| | - Yuta Ochi
- Laboratory for Biofunction Dynamics Imaging, RIKEN Center for Biosystems Dynamics Research 6-7-3 Minatojima-minamimachi, Chuo-ku Kobe Hyogo 650-0047 Japan
| | - Daisuke Kano
- Pharmaceutical department, National Cancer Center Hospital East 6-5-1 Kashiwanoha, Kashiwa-shi Chiba 277-8577 Japan
| | - Ukihide Tateishi
- Department of Diagnostic Radiology and Nuclear Medicine, Tokyo Medical and Dental University Graduate School of Medicine 1-5-45, Yushima, Bunkyo-ku Tokyo 113-8519 Japan
| | - Yasuyoshi Watanabe
- Laboratory for Pathophysiological and Health Science, RIKEN Center for Biosystems Dynamics Research 6-7-3 Minatojima-minamimachi, Chuo-ku Kobe Hyogo 650-0047 Japan
| | - Yilong Cui
- Laboratory for Biofunction Dynamics Imaging, RIKEN Center for Biosystems Dynamics Research 6-7-3 Minatojima-minamimachi, Chuo-ku Kobe Hyogo 650-0047 Japan
| | - Yasuo Mori
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University Nishikyo-ku Kyoto 615-8510 Japan
| | - Hisashi Doi
- Laboratory for Labeling Chemistry, RIKEN Center for Biosystems Dynamics Research 6-7-3 Minatojima-minamimachi, Chuo-ku Kobe Hyogo 650-0047 Japan
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29
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The human TRPA1 intrinsic cold and heat sensitivity involves separate channel structures beyond the N-ARD domain. Nat Commun 2022; 13:6113. [PMID: 36253390 PMCID: PMC9576766 DOI: 10.1038/s41467-022-33876-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 10/04/2022] [Indexed: 12/24/2022] Open
Abstract
TRP channels sense temperatures ranging from noxious cold to noxious heat. Whether specialized TRP thermosensor modules exist and how they control channel pore gating is unknown. We studied purified human TRPA1 (hTRPA1) truncated proteins to gain insight into the temperature gating of hTRPA1. In patch-clamp bilayer recordings, ∆1-688 hTRPA1, without the N-terminal ankyrin repeat domain (N-ARD), was more sensitive to cold and heat, whereas ∆1-854 hTRPA1, also lacking the S1-S4 voltage sensing-like domain (VSLD), gained sensitivity to cold but lost its heat sensitivity. In hTRPA1 intrinsic tryptophan fluorescence studies, cold and heat evoked rearrangement of VSLD and the C-terminus domain distal to the transmembrane pore domain S5-S6 (CTD). In whole-cell electrophysiology experiments, replacement of the CTD located cysteines 1021 and 1025 with alanine modulated hTRPA1 cold responses. It is proposed that hTRPA1 CTD harbors cold and heat sensitive domains allosterically coupled to the S5-S6 pore region and the VSLD, respectively.
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30
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Wei Y, Cai J, Zhu R, Xu K, Li H, Li J. Function and therapeutic potential of transient receptor potential ankyrin 1 in fibrosis. Front Pharmacol 2022; 13:1014041. [PMID: 36278189 PMCID: PMC9582847 DOI: 10.3389/fphar.2022.1014041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 09/26/2022] [Indexed: 11/18/2022] Open
Abstract
The transient receptor potential (TRP) protein superfamily is a special group of cation channels expressed in different cell types and signaling pathways. In this review, we focus on TRPA1 (transient receptor potential ankyrin 1), an ion channel in this family that exists in the cell membrane and shows a different function from other TRP channels. TRPA1 usually has a special activation effect that can induce cation ions, especially calcium ions, to flow into activated cells. In this paper, we review the role of TRPA1 in fibroblasts. To clarify the relationship between fibroblasts and TRPA1, we have also paid special attention to the interactions between TRPA1 and inflammatory factors leading to fibroblast activation. TRPA1 has different functions in the fibrosis process in different organs, and there have also been interesting discussions of the mechanism of TRPA1 in fibroblasts. Therefore, this review aims to describe the function of TRP channels in controlling fibrosis through fibroblasts in different organ inflammatory and immune-mediated diseases. We attempt to prove that TRPA1 is a target for fibrosis. In fact, some clinical trials have already proven that TRPA1 is a potential adjuvant therapy for treating fibrosis.
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Affiliation(s)
- Yicheng Wei
- Third Affiliated Hospital of Shanghai University/Wenzhou People’s Hospital, Wenzhou, China
- Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jialuo Cai
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Ruiqiu Zhu
- Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ke Xu
- Musculoskeletal Organoid Research Center, Institute of Translational Medicine, Shanghai University, Shanghai, China
- Wenzhou Institute of Shanghai University, Wenzhou, China
- *Correspondence: Ke Xu, , ; Hongchang Li, ; Jianxin Li,
| | - Hongchang Li
- Department of General Surgery, Institute of Fudan–Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, China
- *Correspondence: Ke Xu, , ; Hongchang Li, ; Jianxin Li,
| | - Jianxin Li
- Third Affiliated Hospital of Shanghai University/Wenzhou People’s Hospital, Wenzhou, China
- *Correspondence: Ke Xu, , ; Hongchang Li, ; Jianxin Li,
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Abstract
Mice with insulin receptor (IR)-deficient astrocytes (GFAP-IR knockout [KO] mice) show blunted responses to insulin and reduced brain glucose uptake, whereas IR-deficient astrocytes show disturbed mitochondrial responses to glucose. While exploring the functional impact of disturbed mitochondrial function in astrocytes, we observed that GFAP-IR KO mice show uncoupling of brain blood flow with glucose uptake. Since IR-deficient astrocytes show higher levels of reactive oxidant species (ROS), this leads to stimulation of hypoxia-inducible factor-1α and, consequently, of the vascular endothelial growth factor angiogenic pathway. Indeed, GFAP-IR KO mice show disturbed brain vascularity and blood flow that is normalized by treatment with the antioxidant N-acetylcysteine (NAC). NAC ameliorated high ROS levels, normalized angiogenic signaling and mitochondrial function in IR-deficient astrocytes, and normalized neurovascular coupling in GFAP-IR KO mice. Our results indicate that by modulating glucose uptake and angiogenesis, insulin receptors in astrocytes participate in neurovascular coupling.
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32
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Audero MM, Prevarskaya N, Fiorio Pla A. Ca 2+ Signalling and Hypoxia/Acidic Tumour Microenvironment Interplay in Tumour Progression. Int J Mol Sci 2022; 23:7377. [PMID: 35806388 PMCID: PMC9266881 DOI: 10.3390/ijms23137377] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/26/2022] [Accepted: 06/27/2022] [Indexed: 01/18/2023] Open
Abstract
Solid tumours are characterised by an altered microenvironment (TME) from the physicochemical point of view, displaying a highly hypoxic and acidic interstitial fluid. Hypoxia results from uncontrolled proliferation, aberrant vascularization and altered cancer cell metabolism. Tumour cellular apparatus adapts to hypoxia by altering its metabolism and behaviour, increasing its migratory and metastatic abilities by the acquisition of a mesenchymal phenotype and selection of aggressive tumour cell clones. Extracellular acidosis is considered a cancer hallmark, acting as a driver of cancer aggressiveness by promoting tumour metastasis and chemoresistance via the selection of more aggressive cell phenotypes, although the underlying mechanism is still not clear. In this context, Ca2+ channels represent good target candidates due to their ability to integrate signals from the TME. Ca2+ channels are pH and hypoxia sensors and alterations in Ca2+ homeostasis in cancer progression and vascularization have been extensively reported. In the present review, we present an up-to-date and critical view on Ca2+ permeable ion channels, with a major focus on TRPs, SOCs and PIEZO channels, which are modulated by tumour hypoxia and acidosis, as well as the consequent role of the altered Ca2+ signals on cancer progression hallmarks. We believe that a deeper comprehension of the Ca2+ signalling and acidic pH/hypoxia interplay will break new ground for the discovery of alternative and attractive therapeutic targets.
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Affiliation(s)
- Madelaine Magalì Audero
- U1003—PHYCEL—Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, Villeneuve d’Ascq, 59000 Lille, France; (M.M.A.); (N.P.)
- Laboratory of Cellular and Molecular Angiogenesis, Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy
| | - Natalia Prevarskaya
- U1003—PHYCEL—Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, Villeneuve d’Ascq, 59000 Lille, France; (M.M.A.); (N.P.)
| | - Alessandra Fiorio Pla
- U1003—PHYCEL—Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, Villeneuve d’Ascq, 59000 Lille, France; (M.M.A.); (N.P.)
- Laboratory of Cellular and Molecular Angiogenesis, Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy
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Chen P, Liu Y, Liu W, Wang Y, Liu Z, Rong M. Impact of High-Altitude Hypoxia on Bone Defect Repair: A Review of Molecular Mechanisms and Therapeutic Implications. Front Med (Lausanne) 2022; 9:842800. [PMID: 35620712 PMCID: PMC9127390 DOI: 10.3389/fmed.2022.842800] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 04/15/2022] [Indexed: 11/23/2022] Open
Abstract
Reaching areas at altitudes over 2,500–3,000 m above sea level has become increasingly common due to commerce, military deployment, tourism, and entertainment. The high-altitude environment exerts systemic effects on humans that represent a series of compensatory reactions and affects the activity of bone cells. Cellular structures closely related to oxygen-sensing produce corresponding functional changes, resulting in decreased tissue vascularization, declined repair ability of bone defects, and longer healing time. This review focuses on the impact of high-altitude hypoxia on bone defect repair and discusses the possible mechanisms related to ion channels, reactive oxygen species production, mitochondrial function, autophagy, and epigenetics. Based on the key pathogenic mechanisms, potential therapeutic strategies have also been suggested. This review contributes novel insights into the mechanisms of abnormal bone defect repair in hypoxic environments, along with therapeutic applications. We aim to provide a foundation for future targeted, personalized, and precise bone regeneration therapies according to the adaptation of patients to high altitudes.
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Affiliation(s)
- Pei Chen
- Department of Periodontology and Implantology, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Yushan Liu
- Department of Periodontology and Implantology, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Wenjing Liu
- Department of Prosthodontics, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Yarong Wang
- Department of Periodontology and Implantology, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Ziyi Liu
- Department of Periodontology and Implantology, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Mingdeng Rong
- Department of Periodontology and Implantology, Stomatological Hospital, Southern Medical University, Guangzhou, China
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Camponogara C, Oliveira SM. Are TRPA1 and TRPV1 channel-mediated signalling cascades involved in UVB radiation-induced sunburn? ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2022; 92:103836. [PMID: 35248760 DOI: 10.1016/j.etap.2022.103836] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 02/09/2022] [Accepted: 02/28/2022] [Indexed: 06/14/2023]
Abstract
Burn injuries are underappreciated injuries associated with substantial morbidity and mortality. Overexposure to ultraviolet (UV) radiation has dramatic clinical effects in humans and is a significant public health concern. Although the mechanisms underlying UVB exposure are not fully understood, many studies have made substantial progress in the pathophysiology of sunburn in terms of its molecular aspects in the last few years. It is well established that the transient receptor potential ankyrin 1 (TRPA1), and vanilloid 1 (TRPV1) channels modulate the inflammatory, oxidative, and proliferative processes underlying UVB radiation exposure. However, it is still unknown which mechanisms underlying TRPV1/A1 channel activation are elicited in sunburn induced by UVB radiation. Therefore, in this review, we give an overview of the TRPV1/A1 channel-mediated signalling cascades that may be involved in the pathophysiology of sunburn induced by UVB radiation. These data will undoubtedly help to explain the various features of sunburn and contribute to the development of novel therapeutic approaches to better treat it.
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Affiliation(s)
- Camila Camponogara
- Graduated Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Sara Marchesan Oliveira
- Graduated Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, Santa Maria, RS, Brazil; Department of Biochemistry and Molecular Biology, Centre of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, Brazil.
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Zhong T, Zhang W, Guo H, Pan X, Chen X, He Q, Yang B, Ding L. The regulatory and modulatory roles of TRP family channels in malignant tumors and relevant therapeutic strategies. Acta Pharm Sin B 2022; 12:1761-1780. [PMID: 35847486 PMCID: PMC9279634 DOI: 10.1016/j.apsb.2021.11.001] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 09/11/2021] [Accepted: 10/19/2021] [Indexed: 02/08/2023] Open
Abstract
Transient receptor potential (TRP) channels are one primary type of calcium (Ca2+) permeable channels, and those relevant transmembrane and intracellular TRP channels were previously thought to be mainly associated with the regulation of cardiovascular and neuronal systems. Nowadays, however, accumulating evidence shows that those TRP channels are also responsible for tumorigenesis and progression, inducing tumor invasion and metastasis. However, the overall underlying mechanisms and possible signaling transduction pathways that TRP channels in malignant tumors might still remain elusive. Therefore, in this review, we focus on the linkage between TRP channels and the significant characteristics of tumors such as multi-drug resistance (MDR), metastasis, apoptosis, proliferation, immune surveillance evasion, and the alterations of relevant tumor micro-environment. Moreover, we also have discussed the expression of relevant TRP channels in various forms of cancer and the relevant inhibitors' efficacy. The chemo-sensitivity of the anti-cancer drugs of various acting mechanisms and the potential clinical applications are also presented. Furthermore, it would be enlightening to provide possible novel therapeutic approaches to counteract malignant tumors regarding the intervention of calcium channels of this type.
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Key Words
- 4α-PDD, 4α-phorbol-12,13-didecanoate
- ABCB, ATP-binding cassette B1
- AKT, protein kinase B
- ALA, alpha lipoic acid
- AMPK, AMP-activated protein kinase
- APB, aminoethoxydiphenyl borate
- ATP, adenosine triphosphate
- CBD, cannabidiol
- CRAC, Ca2+ release-activated Ca2+ channel
- CaR, calcium-sensing receptor
- CaSR, calcium sensing receptor
- Cancer progression
- DAG, diacylglycerol
- DBTRG, Denver Brain Tumor Research Group
- ECFC, endothelial colony-forming cells
- ECM, enhanced extracellular matrix
- EGF, epidermal growth factor
- EMT, epithelial–mesenchymal transition
- ER, endoplasmic reticulum
- ERK, extracellular signal-regulated kinase
- ETS, erythroblastosis virus E26 oncogene homolog
- FAK, focal adhesion kinase
- GADD, growth arrest and DNA damage-inducible gene
- GC, gastric cancer
- GPCR, G-protein coupled receptor
- GSC, glioma stem-like cells
- GSK, glycogen synthase kinase
- HCC, hepatocellular carcinoma
- HIF, hypoxia-induced factor
- HSC, hematopoietic stem cells
- IP3R, inositol triphosphate receptor
- Intracellular mechanism
- KO, knockout
- LOX, lipoxygenase
- LPS, lipopolysaccharide
- LRP, lipoprotein receptor-related protein
- MAPK, mitogen-activated protein kinase
- MLKL, mixed lineage kinase domain-like protein
- MMP, matrix metalloproteinases
- NEDD4, neural precursor cell expressed, developmentally down-regulated 4
- NFAT, nuclear factor of activated T-cells
- NLRP3, NLR family pyrin domain containing 3
- NO, nitro oxide
- NSCLC, non-small cell lung cancer
- Nrf2, nuclear factor erythroid 2-related factor 2
- P-gp, P-glycoprotein
- PCa, prostate cancer
- PDAC, pancreatic ductal adenocarcinoma
- PHD, prolyl hydroxylases
- PI3K, phosphoinositide 3-kinase
- PKC, protein kinase C
- PKD, polycystic kidney disease
- PLC, phospholipase C
- Programmed cancer cell death
- RNS/ROS, reactive nitrogen species/reactive oxygen species
- RTX, resiniferatoxin
- SMAD, Caenorhabditis elegans protein (Sma) and mothers against decapentaplegic (Mad)
- SOCE, store operated calcium entry
- SOR, soricimed
- STIM1, stromal interaction molecules 1
- TEC, tumor endothelial cells
- TGF, transforming growth factor-β
- TNF-α, tumor necrosis factor-α
- TRP channels
- TRPA/C/M/ML/N/P/V, transient receptor potential ankyrin/canonical/melastatin/mucolipon/NOMPC/polycystin/vanilloid
- Targeted tumor therapy
- Tumor microenvironment
- Tumor-associated immunocytes
- UPR, unfolded protein response
- VEGF, vascular endothelial growth factor
- VIP, vasoactive intestinal peptide
- VPAC, vasoactive intestinal peptide receptor subtype
- mTOR, mammalian target of rapamycin
- pFRG/RTN, parafacial respiratory group/retrotrapezoid nucleus
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Barioni NO, Derakhshan F, Tenorio Lopes L, Onimaru H, Roy A, McDonald F, Scheibli E, Baghdadwala MI, Heidari N, Bharadia M, Ikeda K, Yazawa I, Okada Y, Harris MB, Dutschmann M, Wilson RJA. Novel oxygen sensing mechanism in the spinal cord involved in cardiorespiratory responses to hypoxia. SCIENCE ADVANCES 2022; 8:eabm1444. [PMID: 35333571 PMCID: PMC8956269 DOI: 10.1126/sciadv.abm1444] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 02/04/2022] [Indexed: 05/05/2023]
Abstract
As blood oxygenation decreases (hypoxemia), mammals mount cardiorespiratory responses, increasing oxygen to vital organs. The carotid bodies are the primary oxygen chemoreceptors for breathing, but sympathetic-mediated cardiovascular responses to hypoxia persist in their absence, suggesting additional high-fidelity oxygen sensors. We show that spinal thoracic sympathetic preganglionic neurons are excited by hypoxia and silenced by hyperoxia, independent of surrounding astrocytes. These spinal oxygen sensors (SOS) enhance sympatho-respiratory activity induced by CNS asphyxia-like stimuli, suggesting they bestow a life-or-death advantage. Our data suggest the SOS use a mechanism involving neuronal nitric oxide synthase 1 (NOS1) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). We propose NOS1 serves as an oxygen-dependent sink for NADPH in hyperoxia. In hypoxia, NADPH catabolism by NOS1 decreases, increasing availability of NADPH to NOX and launching reactive oxygen species-dependent processes, including transient receptor potential channel activation. Equipped with this mechanism, SOS are likely broadly important for physiological regulation in chronic disease, spinal cord injury, and cardiorespiratory crisis.
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Affiliation(s)
- Nicole O. Barioni
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Fatemeh Derakhshan
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Luana Tenorio Lopes
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Hiroshi Onimaru
- Department of Physiology, Showa University School of Medicine, Tokyo, Japan
| | - Arijit Roy
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Fiona McDonald
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Erika Scheibli
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Mufaddal I. Baghdadwala
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Negar Heidari
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Manisha Bharadia
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Keiko Ikeda
- Division of Internal Medicine, Murayama Medical Center, Musashimurayama, Tokyo, Japan
| | - Itaru Yazawa
- Global Research Center for Innovative Life Science, Peptide Drug Innovation, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo 142-8501, Japan
| | - Yasumasa Okada
- Division of Internal Medicine, Murayama Medical Center, Musashimurayama, Tokyo, Japan
| | - Michael B. Harris
- Department of Biological Sciences, California State University Long Beach, Long Beach, CA 90840, USA
| | - Mathias Dutschmann
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, 3052, Australia
| | - Richard J. A. Wilson
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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Abstract
Animals rely on their sensory systems to inform them of ecologically relevant environmental variation. In the Southern Ocean, the thermal environment has remained between −1.9 and 5 °C for 15 Myr, yet we have no knowledge of how an Antarctic marine organism might sense their thermal habitat as we have yet to discover a thermosensitive ion channel that gates (opens/closes) below 10 °C. Here, we investigate the evolutionary dynamics of transient receptor potential (TRP) channels, which are the primary thermosensors in animals, within cryonotothenioid fishes—the dominant fish fauna of the Southern Ocean. We found cryonotothenioids have a similar complement of TRP channels as other teleosts (∼28 genes). Previous work has shown that thermosensitive gating in a given channel is species specific, and multiple channels act together to sense the thermal environment. Therefore, we combined evidence of changes in selective pressure, gene gain/loss dynamics, and the first sensory ganglion transcriptome in this clade to identify the best candidate TRP channels that might have a functional dynamic range relevant for frigid Antarctic temperatures. We concluded that TRPV1a, TRPA1b, and TRPM4 are the likeliest putative thermosensors, and found evidence of diversifying selection at sites across these proteins. We also put forward hypotheses for molecular mechanisms of other cryonotothenioid adaptations, such as reduced skeletal calcium deposition, sensing oxidative stress, and unusual magnesium homeostasis. By completing a comprehensive and unbiased survey of these genes, we lay the groundwork for functional characterization and answering long-standing thermodynamic questions of thermosensitive gating and protein adaptation to low temperatures.
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Affiliation(s)
- Julia M York
- Department of Integrative Biology, University of Texas at Austin, USA
- Corresponding author: E-mail:
| | - Harold H Zakon
- Department of Integrative Biology, University of Texas at Austin, USA
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Nakatomi C, Hitomi S, Yamaguchi K, Hsu CC, Seta Y, Harano N, Iwata K, Ono K. Cisplatin induces TRPA1-mediated mechanical allodynia in the oral mucosa. Arch Oral Biol 2021; 133:105317. [PMID: 34823152 DOI: 10.1016/j.archoralbio.2021.105317] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 11/08/2021] [Accepted: 11/13/2021] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Cisplatin, a platinum-based anticancer drug, produces reactive oxygen species (ROS) in many cell types and induces mechanical allodynia in the hands and/or feet (chemotherapy-induced painful neuropathy: CIPN). In this study, we examined the possibility of inducing neuropathy in the oral region using oral keratinocytes and rats. METHODS Human oral keratinocytes (HOKs) were used to evaluate ROS generation after cisplatin application by a ROS-reactive fluorescent assay. In rats, after cisplatin administrations (two times), the trigeminal ganglion (TG) was investigated by electron microscopy and quantitative RT-PCR. Using our proprietary assay system, oral pain-related behaviors were observed in cisplatin-treated rats. RESULTS In rats, cisplatin administration reduced food intake and body weight. In electron microscopic analysis, glycogen granules in the TG were depleted following administration, although organelles were intact. In HOK cells, cisplatin significantly increased ROS generation with cell death, similar to glycolysis inhibitors. Cisplatin administration did not show any effects on Trpa1 mRNA levels in the TG. However, the same procedure induced hypersensitivity to mechanical stimulation and the TRPA1 agonist allyl isothiocyanate in the oral mucosa. Mechanical hypersensitivity was inhibited by the antioxidative drug α-lipoic acid and the TRPA1 antagonist HC-030031, similar to that of the hind paw. CONCLUSION The present findings suggest that cisplatin induces TRPA1-mediated CIPN due to ROS generation in the oral region. This study will provide a better understanding of persistent oral pain in cancer patients.
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Affiliation(s)
- Chihiro Nakatomi
- Division of Physiology, Kyushu Dental University, Fukuoka, Japan
| | - Suzuro Hitomi
- Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan
| | | | - Chia-Chien Hsu
- Division of Physiology, Kyushu Dental University, Fukuoka, Japan
| | - Yuji Seta
- Division of Anatomy, Kyushu Dental University, Fukuoka, Japan
| | - Nozomu Harano
- Division of Dental Anesthesiology, Kyushu Dental University, Fukuoka, Japan
| | - Koichi Iwata
- Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan
| | - Kentaro Ono
- Division of Physiology, Kyushu Dental University, Fukuoka, Japan.
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Fukushi I, Takeda K, Pokorski M, Kono Y, Yoshizawa M, Hasebe Y, Nakao A, Mori Y, Onimaru H, Okada Y. Activation of Astrocytes in the Persistence of Post-hypoxic Respiratory Augmentation. Front Physiol 2021; 12:757731. [PMID: 34690820 PMCID: PMC8531090 DOI: 10.3389/fphys.2021.757731] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 09/15/2021] [Indexed: 11/16/2022] Open
Abstract
Acute hypoxia increases ventilation. After cessation of hypoxia loading, ventilation decreases but remains above the pre-exposure baseline level for a time. However, the mechanism of this post-hypoxic persistent respiratory augmentation (PHRA), which is a short-term potentiation of breathing, has not been elucidated. We aimed to test the hypothesis that astrocytes are involved in PHRA. To this end, we investigated hypoxic ventilatory responses by whole-body plethysmography in unanesthetized adult mice. The animals breathed room air, hypoxic gas mixture (7% O2, 93% N2) for 2min, and again room air for 10min before and after i.p. administration of low (100mg/kg) and high (300mg/kg) doses of arundic acid (AA), an astrocyte inhibitor. AA suppressed PHRA, with the high dose decreasing ventilation below the pre-hypoxic level. Further, we investigated the role of the astrocytic TRPA1 channel, a putative ventilatory hypoxia sensor, in PHRA using astrocyte-specific Trpa1 knockout (asTrpa1−/−) and floxed Trpa1 (Trpa1f/f) mice. In both Trpa1f/f and asTrpa1−/− mice, PHRA was noticeable, indicating that the astrocyte TRPA1 channel was not directly involved in PHRA. Taken together, these results indicate that astrocytes mediate the PHRA by mechanisms other than TRPA1 channels that are engaged in hypoxia sensing.
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Affiliation(s)
- Isato Fukushi
- Faculty of Health Sciences, Uekusa Gakuen University, Chiba, Japan.,Clinical Research Center, Murayama Medical Center, Musashimurayama, Japan
| | - Kotaro Takeda
- Clinical Research Center, Murayama Medical Center, Musashimurayama, Japan.,Faculty of Rehabilitation, School of Healthcare, Fujita Health University, Toyoake, Japan
| | - Mieczyslaw Pokorski
- Institute of Health Sciences, University of Opole, Opole, Poland.,Faculty of Health Sciences, The Jan Dlugosz University in Czestochowa, Czestochowa, Poland
| | - Yosuke Kono
- Clinical Research Center, Murayama Medical Center, Musashimurayama, Japan.,Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Masashi Yoshizawa
- Clinical Research Center, Murayama Medical Center, Musashimurayama, Japan.,Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Yohei Hasebe
- Clinical Research Center, Murayama Medical Center, Musashimurayama, Japan.,Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Akito Nakao
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Yasuo Mori
- Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Hiroshi Onimaru
- Department of Physiology, Showa University School of Medicine, Tokyo, Japan
| | - Yasumasa Okada
- Clinical Research Center, Murayama Medical Center, Musashimurayama, Japan
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Evidence That a TRPA1-Mediated Murine Model of Temporomandibular Joint Pain Involves NLRP3 Inflammasome Activation. Pharmaceuticals (Basel) 2021; 14:ph14111073. [PMID: 34832855 PMCID: PMC8622821 DOI: 10.3390/ph14111073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/14/2021] [Accepted: 10/14/2021] [Indexed: 11/17/2022] Open
Abstract
This study investigates the role of transient receptor potential ankyrin 1 (TRPA1) in murine temporomandibular joint (TMJ) inflammatory hyperalgesia and the influence of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. Two distinct murine models of TMJ pain and inflammation (zymosan and CFA) were established. Spontaneous pain-like behaviours were observed as unilateral front paw cheek wipes. Ipsilateral cheek blood flow was used as a measure of ongoing inflammation, which, to our knowledge, is a novel approach to assessing real-time inflammation in the TMJ. Joint tissue and trigeminal ganglia were collected for ex vivo investigation. Both zymosan and CFA induced a time-dependent increase in hyperalgesia and inflammation biomarkers. Zymosan induced a significant effect after 4 h, correlating with a significantly increased IL-1β protein expression. CFA (50 µg) induced a more sustained response. The TRPA1 receptor antagonist A967079 significantly inhibited hyper-nociception. The NLRP3 inhibitor MCC950 similarly inhibited hyper-nociception, also attenuating inflammatory markers. In the trigeminal ganglia, CFA-induced CGRP expression showed trends of inhibition by A967079, whilst lba1 immunofluorescence was significantly inhibited by A967079 and MCC950, where the effect of TRPA1 inhibition lasted up to 14 days. Our results show that stimulation of TRPA1 is key to the TMJ pain. However, the inflammasome inhibitor exhibited similar properties in attenuating these pain-like behaviours, in addition to some inflammatory markers. This indicates that in addition to the therapeutic targeting of TRPA1, NLRP3 inhibition may provide a novel therapeutic strategy for TMJ inflammation and pain.
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Liu L, Liu X, Liu M, Xie D, Yan H. Proline hydroxylase domain-containing enzymes regulate calcium levels in cardiomyocytes by TRPA1 ion channel. Exp Cell Res 2021; 407:112777. [PMID: 34389294 DOI: 10.1016/j.yexcr.2021.112777] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 07/01/2021] [Accepted: 08/07/2021] [Indexed: 11/15/2022]
Abstract
The proline hydroxylase domain-containing enzymes (PHDs) acts as cellular oxygen sensors, inducing a series of responses to hypoxia, especially during the regulation of metabolism and energy homeostasis. The increase of Ca2+ in cardiomyocytes, induced by the opening of PHD signaling pathway, is the key initiation signal necessary for the PHD-mediated regulation of the energy metabolism pathway, but the underlying molecular mechanism remains incompletely understood. This study used PHD inhibitors (PHIs) and PHD2-specific RNA interference (PHD2shRNA) to inhibit PHD signals in cardiomyocytes to explore whether transient receptor potential ankyrin 1 (TRPA1) is involved in the regulation of calcium ion influx in the PHD activation pathway associated with to AMP-activated protein kinase (AMPK). The Fluo-3AM probe was used to measure changes in free intracellular calcium ion concentrations, and western blot analysis was used to detect the levels of phosphorylated (P)-AMPK, TRPA1, and P-Ca2+/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) levels. The PHI-mediated inhibition of PHD resulted in an increase in free Ca2+ fluorescence in cardiomyocytes, which activated AMPK, TRPA1, and CaMKⅡ. The TRPA1 inhibitor HC030031, the CaMKII inhibitor KN93, and a ryanodine inhibitor (Ryanodine) were all able to inhibit the PHI-induced increase in intracellular Ca2+ and AMPK activation. Both PHIs and PHD2shRNA were able to effectively activate CaMKII and TRPA1. However, an inositol 1,4,5-triphosphate receptor (IP3R) inhibitor and the protein kinase A (PKA) inhibitor H89 did not significantly inhibit the PHI-induced increase in intracellular Ca2+ and AMPK activation. These results indicated that PHD might activate the CaMKⅡ pathway through the TRPA1 ion channel, inducing the release of calcium from the sarcoplasmic reticulum through ryanodine receptor 2 (RyR2), activating AMPK to initiate the protective effects of hypoxia in cardiomyocytes.
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Affiliation(s)
- Lan Liu
- Department of Plastic and Burn Surgery, Affiliated Hospital of Southwest Medical University, National Key Clinical Construction Specialty, Wound Repair and Regeneration Laboratory, Luzhou, Sichuan Province, 646000, China
| | - Xingke Liu
- Department of Plastic and Burn Surgery, Affiliated Hospital of Southwest Medical University, National Key Clinical Construction Specialty, Wound Repair and Regeneration Laboratory, Luzhou, Sichuan Province, 646000, China
| | - Mengchang Liu
- Department of Plastic and Burn Surgery, Affiliated Hospital of Southwest Medical University, National Key Clinical Construction Specialty, Wound Repair and Regeneration Laboratory, Luzhou, Sichuan Province, 646000, China
| | - Defu Xie
- Department of Plastic and Burn Surgery, Affiliated Hospital of Southwest Medical University, National Key Clinical Construction Specialty, Wound Repair and Regeneration Laboratory, Luzhou, Sichuan Province, 646000, China
| | - Hong Yan
- Department of Plastic and Burn Surgery, Affiliated Hospital of Southwest Medical University, National Key Clinical Construction Specialty, Wound Repair and Regeneration Laboratory, Luzhou, Sichuan Province, 646000, China.
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Jia Q, Tian W, Li B, Chen W, Zhang W, Xie Y, Cheng N, Chen Q, Xiao J, Zhang Y, Yang J, Wang S. TRPV1 and TRPA1 in melanocytes synergize UV-dependent and UV-independent melanogenesis. Br J Pharmacol 2021; 178:4646-4662. [PMID: 34363226 DOI: 10.1111/bph.15643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 07/18/2021] [Accepted: 07/21/2021] [Indexed: 10/20/2022] Open
Abstract
BACKGROUND AND PURPOSE Melanogenesis is essential for pigmentation, and deregulated melanogenesis causes pigmentary diseases. PUVA therapy (psoralen plus ultraviolet A, UVA) strongly stimulates pigmentation, but the underlying molecular mechanisms are elusive. EXPERIMENTAL APPROACH Melanin content of cultured human melanocytes was spectrophotometrically measured. Patch-clamp recordings were made in human melanocytes or HEK 293 cells transiently expressing wild type or mutant human TRPV1 and TRPA1 channels. Endogenous expression of TRPV1 and TRPA1 in melanocytes was analyzed by western blotting and was knocked down with siRNA. In vivo pigmentary responses were measured by a colorimeter in mouse ear skin. The expression of TRPV1 and TRPA1 in human pigmented lesions was examined by immunohistochemical staining. KEY RESULTS PUVA strongly stimulated melanogenesis, and PUVA-induced TRPV1 and TRPA1 channel activation in melanocytes and the resulting Ca2+ influx were required for the stimulated melanogenesis both in vitro and in vivo. Agonists-induced TRPV1 and TRPA1 activation alone did not stimulate melanogenesis, but it synergized UVA or intrinsic cAMP and NO signaling pathways to stimulate UV-dependent or UV-independent melanogenesis. Moreover, the expressions of TRPV1 and TRPA1 were increased in human melanocytic lesions, and inhibition of both channels decreased melanin content in melanoma cells. CONCLUSION AND IMPLICATIONS TRPV1 and TRPA1 are key molecular sensors and enhancers of extrinsic and intrinsic melanogenic signals in both physiological and pathological conditions, and activation of both channels in melanocytes contributes to PUVA therapy-induced pigmentation. Our work provides a common mechanism of melanogenic regulation and highlights TRPV1 and TRPA1 as potential therapeutic targets for pigmentary disorders.
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Affiliation(s)
- Qi Jia
- Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.,Department of Orthopedic Oncology, Changzheng Hospital, Navy Medical University, Shanghai, China
| | - Weifeng Tian
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, and Ion Channel Research and Drug Development Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China
| | - Binbin Li
- Department of Pathology, Changzheng Hospital, Navy Medical University, Shanghai, China
| | - Wen Chen
- Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Wenjie Zhang
- Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Yang Xie
- Department of Dermatology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Na Cheng
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qi Chen
- Department of Biostatistics, Navy Medical University, Shanghai, China
| | - Jianru Xiao
- Department of Orthopedic Oncology, Changzheng Hospital, Navy Medical University, Shanghai, China
| | - Yiwang Zhang
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jian Yang
- Department of Biological Sciences, Columbia University, New York, NY, USA
| | - Shu Wang
- Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
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Iturriaga R, Alcayaga J, Chapleau MW, Somers VK. Carotid body chemoreceptors: physiology, pathology, and implications for health and disease. Physiol Rev 2021; 101:1177-1235. [PMID: 33570461 PMCID: PMC8526340 DOI: 10.1152/physrev.00039.2019] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The carotid body (CB) is the main peripheral chemoreceptor for arterial respiratory gases O2 and CO2 and pH, eliciting reflex ventilatory, cardiovascular, and humoral responses to maintain homeostasis. This review examines the fundamental biology underlying CB chemoreceptor function, its contribution to integrated physiological responses, and its role in maintaining health and potentiating disease. Emphasis is placed on 1) transduction mechanisms in chemoreceptor (type I) cells, highlighting the role played by the hypoxic inhibition of O2-dependent K+ channels and mitochondrial oxidative metabolism, and their modification by intracellular molecules and other ion channels; 2) synaptic mechanisms linking type I cells and petrosal nerve terminals, focusing on the role played by the main proposed transmitters and modulatory gases, and the participation of glial cells in regulation of the chemosensory process; 3) integrated reflex responses to CB activation, emphasizing that the responses differ dramatically depending on the nature of the physiological, pathological, or environmental challenges, and the interactions of the chemoreceptor reflex with other reflexes in optimizing oxygen delivery to the tissues; and 4) the contribution of enhanced CB chemosensory discharge to autonomic and cardiorespiratory pathophysiology in obstructive sleep apnea, congestive heart failure, resistant hypertension, and metabolic diseases and how modulation of enhanced CB reactivity in disease conditions may attenuate pathophysiology.
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Affiliation(s)
- Rodrigo Iturriaga
- Laboratorio de Neurobiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile, and Centro de Excelencia en Biomedicina de Magallanes, Universidad de Magallanes, Punta Arenas, Chile
| | - Julio Alcayaga
- Laboratorio de Fisiología Celular, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
| | - Mark W Chapleau
- Department of Internal Medicine, University of Iowa and Department of Veterans Affairs Medical Center, Iowa City, Iowa
| | - Virend K Somers
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
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Yoo HY, Kim SJ. Oxygen-dependent regulation of ion channels: acute responses, post-translational modification, and response to chronic hypoxia. Pflugers Arch 2021; 473:1589-1602. [PMID: 34142209 DOI: 10.1007/s00424-021-02590-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 05/15/2021] [Accepted: 05/30/2021] [Indexed: 12/19/2022]
Abstract
Oxygen is a vital element for the survival of cells in multicellular aerobic organisms such as mammals. Lack of O2 availability caused by environmental or pathological conditions leads to hypoxia. Active oxygen distribution systems (pulmonary and circulatory) and their neural control mechanisms ensure that cells and tissues remain oxygenated. However, O2-carrying blood cells as well as immune and various parenchymal cells experience wide variations in partial pressure of oxygen (PO2) in vivo. Hence, the reactive modulation of the functions of the oxygen distribution systems and their ability to sense PO2 are critical. Elucidating the physiological responses of cells to variations in PO2 and determining the PO2-sensing mechanisms at the biomolecular level have attracted considerable research interest in the field of physiology. Herein, we review the current knowledge regarding ion channel-dependent oxygen sensing and associated signalling pathways in mammals. First, we present the recent findings on O2-sensing ion channels in representative chemoreceptor cells as well as in other types of cells such as immune cells. Furthermore, we highlight the transcriptional regulation of ion channels under chronic hypoxia and its physiological implications and summarize the findings of studies on the post-translational modification of ion channels under hypoxic or ischemic conditions.
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Affiliation(s)
- Hae Young Yoo
- Department of Nursing, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Sung Joon Kim
- Department of Physiology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea. .,Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
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45
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Sinica V, Vlachová V. Transient receptor potential ankyrin 1 channel: An evolutionarily tuned thermosensor. Physiol Res 2021; 70:363-381. [PMID: 33982589 DOI: 10.33549/physiolres.934697] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The discovery of the role of the transient receptor potential ankyrin 1 (TRPA1) channel as a polymodal detector of cold and pain-producing stimuli almost two decades ago catalyzed the consequent identification of various vertebrate and invertebrate orthologues. In different species, the role of TRPA1 has been implicated in numerous physiological functions, indicating that the molecular structure of the channel exhibits evolutionary flexibility. Until very recently, information about the critical elements of the temperature-sensing molecular machinery of thermosensitive ion channels such as TRPA1 had lagged far behind information obtained from mutational and functional analysis. Current developments in single-particle cryo-electron microscopy are revealing precisely how the thermosensitive channels operate, how they might be targeted with drugs, and at which sites they can be critically regulated by membrane lipids. This means that it is now possible to resolve a huge number of very important pharmacological, biophysical and physiological questions in a way we have never had before. In this review, we aim at providing some of the recent knowledge on the molecular mechanisms underlying the temperature sensitivity of TRPA1. We also demonstrate how the search for differences in temperature and chemical sensitivity between human and mouse TRPA1 orthologues can be a useful approach to identifying important domains with a key role in channel activation.
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Affiliation(s)
- V Sinica
- Laboratory of Cellular Neurophysiology, Institute of Physiology of the Czech Academy of Sciences, Prague 4, Czech Republic. or
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46
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Alvarado MG, Thakore P, Earley S. Transient Receptor Potential Channel Ankyrin 1: A Unique Regulator of Vascular Function. Cells 2021; 10:cells10051167. [PMID: 34064835 PMCID: PMC8151290 DOI: 10.3390/cells10051167] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/05/2021] [Accepted: 05/09/2021] [Indexed: 12/27/2022] Open
Abstract
TRPA1 (transient receptor potential ankyrin 1), the lone member of the mammalian ankyrin TRP subfamily, is a Ca2+-permeable, non-selective cation channel. TRPA1 channels are localized to the plasma membranes of various cells types, including sensory neurons and vascular endothelial cells. The channel is endogenously activated by byproducts of reactive oxygen species, such as 4-hydroxy-2-noneal, as well as aromatic, dietary molecules including allyl isothiocyanate, a derivative of mustard oil. Several studies have implicated TRPA1 as a regulator of vascular tone that acts through distinct mechanisms. First, TRPA1 on adventitial sensory nerve fibers mediates neurogenic vasodilation by stimulating the release of the vasodilator, calcitonin gene-related peptide. Second, TRPA1 is expressed in the endothelium of the cerebral vasculature, but not in other vascular beds, and its activation results in localized Ca2+ signals that drive endothelium-dependent vasodilation. Finally, TRPA1 is functionally present on brain capillary endothelial cells, where its activation orchestrates a unique biphasic propagation mechanism that dilates upstream arterioles. This response is vital for neurovascular coupling and functional hyperemia in the brain. This review provides a brief overview of the biophysical and pharmacological properties of TRPA1 and discusses the importance of the channel in vascular control and pathophysiology.
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47
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Kashiwadani H, Higa Y, Sugimura M, Kuwaki T. Linalool odor-induced analgesia is triggered by TRPA1-independent pathway in mice. Behav Brain Funct 2021; 17:3. [PMID: 33902628 PMCID: PMC8077846 DOI: 10.1186/s12993-021-00176-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 04/19/2021] [Indexed: 11/10/2022] Open
Abstract
We had recently reported that linalool odor exposure induced significant analgesic effects in mice and that the effects were disappeared in olfactory-deprived mice in which the olfactory epithelium was damaged, thus indicating that the effects were triggered by chemical senses evoked by linalool odor exposure. However, the peripheral neuronal mechanisms, including linalool receptors that contribute toward triggering the linalool odor-induced analgesia, still remain unexplored. In vitro studies have shown that the transient receptor potential ankyrin 1 (TRPA1) responded to linalool, thus raising the possibility that TRPA1 expressed on the trigeminal nerve terminal detects linalool odor inhaled into the nostril and triggers the analgesic effects. To address this hypothesis, we measured the behavioral pain threshold for noxious mechanical stimulation in TRPA1-deficient mice. In contrast to our expectation, we found a significant increase in the threshold after linalool odor exposure in TRPA1-deficient mice, indicating the analgesic effects of linalool odor even in TRPA1-deficient mice. Furthermore, intranasal application of TRPA1 selective antagonist did not alter the analgesic effect of linalool odor. These results showed that the linalool odor-induced analgesia was triggered by a TRPA1-independent pathway in mice.
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Affiliation(s)
- Hideki Kashiwadani
- Department of Physiology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
| | - Yurina Higa
- Department of Physiology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.,Department of Dental Anesthesiology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Mitsutaka Sugimura
- Department of Dental Anesthesiology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Tomoyuki Kuwaki
- Department of Physiology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
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48
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Matsuo T, Isosaka T, Hayashi Y, Tang L, Doi A, Yasuda A, Hayashi M, Lee CY, Cao L, Kutsuna N, Matsunaga S, Matsuda T, Yao I, Setou M, Kanagawa D, Higasa K, Ikawa M, Liu Q, Kobayakawa R, Kobayakawa K. Thiazoline-related innate fear stimuli orchestrate hypothermia and anti-hypoxia via sensory TRPA1 activation. Nat Commun 2021; 12:2074. [PMID: 33824316 PMCID: PMC8024280 DOI: 10.1038/s41467-021-22205-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 02/22/2021] [Indexed: 01/09/2023] Open
Abstract
Thiazoline-related innate fear-eliciting compounds (tFOs) orchestrate hypothermia, hypometabolism, and anti-hypoxia, which enable survival in lethal hypoxic conditions. Here, we show that most of these effects are severely attenuated in transient receptor potential ankyrin 1 (Trpa1) knockout mice. TFO-induced hypothermia involves the Trpa1-mediated trigeminal/vagal pathways and non-Trpa1 olfactory pathway. TFOs activate Trpa1-positive sensory pathways projecting from trigeminal and vagal ganglia to the spinal trigeminal nucleus (Sp5) and nucleus of the solitary tract (NTS), and their artificial activation induces hypothermia. TFO presentation activates the NTS-Parabrachial nucleus pathway to induce hypothermia and hypometabolism; this activation was suppressed in Trpa1 knockout mice. TRPA1 activation is insufficient to trigger tFO-mediated anti-hypoxic effects; Sp5/NTS activation is also necessary. Accordingly, we find a novel molecule that enables mice to survive in a lethal hypoxic condition ten times longer than known tFOs. Combinations of appropriate tFOs and TRPA1 command intrinsic physiological responses relevant to survival fate.
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Affiliation(s)
- Tomohiko Matsuo
- Department of Functional Neuroscience, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan
| | - Tomoko Isosaka
- Department of Functional Neuroscience, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan
| | - Yuichiro Hayashi
- Department of Functional Neuroscience, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan
| | - Lijun Tang
- Department of Functional Neuroscience, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan
| | - Akihiro Doi
- Department of Functional Neuroscience, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan
| | - Aiko Yasuda
- Department of Functional Neuroscience, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan
| | - Mikio Hayashi
- Department of Cellular and Functional Biology, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan
| | - Chia-Ying Lee
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Liqin Cao
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Natsumaro Kutsuna
- Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Chiba, Japan
- LPixel Inc., Tokyo, Japan
| | - Sachihiro Matsunaga
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Chiba, Japan
| | - Takeshi Matsuda
- Department of Optical Imaging, Institute for Medical Photonics Research, PMPERC and IMIC, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Ikuko Yao
- Department of Optical Imaging, Institute for Medical Photonics Research, PMPERC and IMIC, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Mitsuyoshi Setou
- Department of Cellular and Molecular Anatomy and IMIC, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Dai Kanagawa
- Department of Functional Neuroscience, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan
| | - Koichiro Higasa
- Department of Genome Analysis, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan
| | - Masahito Ikawa
- Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Qinghua Liu
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, Japan.
- National Institute of Biological Sciences, Beijing, China.
| | - Reiko Kobayakawa
- Department of Functional Neuroscience, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan.
| | - Ko Kobayakawa
- Department of Functional Neuroscience, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan.
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49
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Gu Q, Lee LY. TRP channels in airway sensory nerves. Neurosci Lett 2021; 748:135719. [PMID: 33587987 PMCID: PMC7988689 DOI: 10.1016/j.neulet.2021.135719] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 02/01/2021] [Accepted: 02/03/2021] [Indexed: 12/12/2022]
Abstract
Transient Receptor Potential (TRP) channels expressed in specific subsets of airway sensory nerves function as transducers and integrators of a diverse range of sensory inputs including chemical, mechanical and thermal signals. These TRP sensors can detect inhaled irritants as well as endogenously released chemical substances. They play an important role in generating the afferent activity carried by these sensory nerves and regulating the centrally mediated pulmonary defense reflexes. Increasing evidence reported in recent investigations has revealed important involvements of several TRP channels (TRPA1, TRPV1, TRPV4 and TRPM8) in the manifestation of various symptoms and pathogenesis of certain acute and chronic airway diseases. This mini-review focuses primarily on these recent findings of the responses of these TRP sensors to the biological stresses emerging under the pathophysiological conditions of the lung and airways.
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Affiliation(s)
- Qihai Gu
- Department of Biomedical Sciences, Mercer University School of Medicine, 1501 Mercer University Drive, Macon, GA, 31207, USA.
| | - Lu-Yuan Lee
- Department of Physiology, University of Kentucky Medical Center, 800 Rose Street, Lexington, KY, 40536-0298, USA.
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Gating of the capsaicin receptor TRPV1 by UVA-light and oxidants are mediated by distinct mechanisms. Cell Calcium 2021; 96:102391. [PMID: 33752082 DOI: 10.1016/j.ceca.2021.102391] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 02/22/2021] [Accepted: 03/09/2021] [Indexed: 02/07/2023]
Abstract
Redox-sensitivity is a common property of several transient receptor potential (TRP) ion channels. Oxidants and UVA-light activate TRPV2 by oxidizing methionine pore residues which are conserved in the capsaicin-receptor TRPV1. However, the redox-sensitivity of TRPV1 is regarded to depend on intracellular cysteine residues. In this study we examined if TRPV1 is gated by UVA-light, and if the conserved methionine residues are relevant for redox-sensitivity of TRPV1. Patch clamp recordings were performed to explore wildtype (WT) and mutants of human TRPV1 (hTRPV1). UVA-light induced hTRPV1-mediated membrane currents and potentiated both proton- and heat-evoked currents. The reducing agent dithiothreitol (DTT) prevented and partially reversed UVA-light induced sensitization of hTRPV1. UVA-light induced sensitization was reduced in the mutant hTRPV1-C158A/C387S/C767S (hTRPV1-3C). The remaining sensitivity to UVA-light of hTRRPV1-3C was not further reduced upon exchange of the methionine residues M568 and M645. While UVA-induced sensitization was reduced in the protein kinase C-insensitive mutant hTRPV1-S502A/S801A, the PKC-inhibitors chelerythrine chloride, staurosporine and Gö6976 did not reduce UVA-induced effects on hTRPV1-WT. While hTRPV1-3C was insensitive to the cysteine-selective oxidant diamide, it displayed a residual sensitivity to H2O2 and chloramine-T. However, the exchange of M568 and M645 in hTRPV1-3C did not further reduce these effects. Our data demonstrate that oxidants and UVA-light gate hTRPV1 by cysteine-dependent as well as cysteine-independent mechanisms. In contrast to TRPV2, the methionine residues 568 and 645 seem to be of limited relevance for redox-sensitivity of hTRPV1. Finally, UVA-light induced gating of hTRPV1 does not seem to require activation of protein kinase C.
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