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Saeed I, Ma L. Transient receptor potential channels and calcium dysregulation: a pathogenic duo in Parkinson's disease. Neural Regen Res 2025; 20:808-810. [PMID: 38886949 PMCID: PMC11433894 DOI: 10.4103/nrr.nrr-d-24-00172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 03/27/2024] [Accepted: 04/21/2024] [Indexed: 06/20/2024] Open
Affiliation(s)
- Iqira Saeed
- Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, QLD, Australia
| | - Linlin Ma
- Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, QLD, Australia
- School of Environment and Science, Griffith University Nathan, Brisbane, QLD, Australia
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2
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Skobeleva K, Wang G, Kaznacheyeva E. STIM Proteins: The Gas and Brake of Calcium Entry in Neurons. Neurosci Bull 2025; 41:305-325. [PMID: 39266936 PMCID: PMC11794855 DOI: 10.1007/s12264-024-01272-5] [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: 01/22/2024] [Accepted: 04/22/2024] [Indexed: 09/14/2024] Open
Abstract
Stromal interaction molecules (STIM)s are Ca2+ sensors in internal Ca2+ stores of the endoplasmic reticulum. They activate the store-operated Ca2+ channels, which are the main source of Ca2+ entry in non-excitable cells. Moreover, STIM proteins interact with other Ca2+ channel subunits and active transporters, making STIMs an important intermediate molecule in orchestrating a wide variety of Ca2+ influxes into excitable cells. Nevertheless, little is known about the role of STIM proteins in brain functioning. Being involved in many signaling pathways, STIMs replenish internal Ca2+ stores in neurons and mediate synaptic transmission and neuronal excitability. Ca2+ dyshomeostasis is a signature of many pathological conditions of the brain, including neurodegenerative diseases, injuries, stroke, and epilepsy. STIMs play a role in these disturbances not only by supporting abnormal store-operated Ca2+ entry but also by regulating Ca2+ influx through other channels. Here, we review the present knowledge of STIMs in neurons and their involvement in brain pathology.
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Affiliation(s)
- Ksenia Skobeleva
- Laboratory of Ion Channels of Cell Membranes, Institute of Cytology, Russian Academy of Sciences, Saint Petersburg, Russia, 194064
| | - Guanghui Wang
- Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Elena Kaznacheyeva
- Laboratory of Ion Channels of Cell Membranes, Institute of Cytology, Russian Academy of Sciences, Saint Petersburg, Russia, 194064.
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Kirstein E, Diebolt CM, Wagner M, Bozzato A, Federspiel JM, Schaudien D, Tschernig T, Englisch CN. Distribution of TRPC1, TRPC3, and TRPC6 in the human thyroid. Pathol Res Pract 2025; 266:155796. [PMID: 39740284 DOI: 10.1016/j.prp.2024.155796] [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: 09/20/2024] [Revised: 12/23/2024] [Accepted: 12/23/2024] [Indexed: 01/02/2025]
Abstract
BACKGROUND Little is known about the protein expression of the transient receptor potential canonical (TRPC) channels 1, 3, and 6 in the thyroid. Research in human tissue is insufficient. Our aim was to investigate the distribution of TRPC1, 3, and 6 in the healthy human thyroid. METHODS Healthy samples were collected from seven nitrite pickling salt-ethanol-polyethylene glycol-fixed cadavers and from one patient who had undergone neck surgery (5 males, 3 females; median = 81.0, interquartile range = 6.5 years). The protein expression profiles of TRPC1, 3, and 6 were assessed using immunohistochemistry with knockout-validated antibodies. A monoclonal calcitonin antibody was used to detect calcitonin-producing C-cells. RESULTS All samples were labeled as healthy, displaying age-appropriate signs of degeneration. TRPC1, 3, and 6 immunolabeling in thyrocytes showed irregular staining patterns leaving selected cells with intense staining, some without. The comparison of calcitonin- and TRPC1-, 3-, and 6-immunolabeled slides strongly suggested TRPC1, 3, and 6 expression in C-cells. Connective tissue showed no immunoreactivity. CONCLUSIONS This is, to the authors' knowledge, the first detailed description of the distribution of these channels in the human thyroid. We conclude that TRPC1, 3, and 6 are expressed in thyrocytes and C-cells of the human thyroid. Further studies are necessary to confirm these small-case-number results and to explore the relevance of these versatile channels in thyroidal health and disease.
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Affiliation(s)
- Emilie Kirstein
- Institute for Anatomy and Cell Biology, Saarland University, Homburg, Saar 66421, Germany
| | - Coline M Diebolt
- Institute for Anatomy and Cell Biology, Saarland University, Homburg, Saar 66421, Germany
| | - Mathias Wagner
- Department of Pathology, Saarland University, Homburg, Saar 66421, Germany
| | - Alessandro Bozzato
- Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, Homburg, Saar 66421, Germany
| | - Jan M Federspiel
- Institute for Legal Medicine, Saarland University, Homburg, Saar 66421, Germany
| | - Dirk Schaudien
- Fraunhofer Institute for Toxicology and Experimental Medicine, Hanover 30625, Germany
| | - Thomas Tschernig
- Institute for Anatomy and Cell Biology, Saarland University, Homburg, Saar 66421, Germany
| | - Colya N Englisch
- Institute for Anatomy and Cell Biology, Saarland University, Homburg, Saar 66421, Germany.
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4
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Wang X, Geng J, Rimal S, Sui Y, Pan J, Qin Z, Lu B. The p53 target DRAM1 modulates calcium homeostasis and ER stress by promoting contact between lysosomes and the ER through STIM1. Proc Natl Acad Sci U S A 2024; 121:e2400531121. [PMID: 39292746 PMCID: PMC11441506 DOI: 10.1073/pnas.2400531121] [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: 01/11/2024] [Accepted: 07/27/2024] [Indexed: 09/20/2024] Open
Abstract
It is well established that DNA Damage Regulated Autophagy Modulator 1 (DRAM1), a lysosomal protein and a target of p53, participates in autophagy. The cellular functions of DRAM1 beyond autophagy remain elusive. Here, we show p53-dependent upregulation of DRAM1 in mitochondrial damage-induced Parkinson's disease (PD) models and exacerbation of disease phenotypes by DRAM1. We find that the lysosomal location of DRAM1 relies on its intact structure including the cytosol-facing C-terminal domain. Excess DRAM1 disrupts endoplasmic reticulum (ER) structure, triggers ER stress, and induces protective ER-phagy. Mechanistically, DRAM1 interacts with stromal interacting molecule 1 (STIM1) to tether lysosomes to the ER and perturb STIM1 function in maintaining intracellular calcium homeostasis. STIM1 overexpression promotes cellular health by restoring calcium homeostasis, ER stress response, ER-phagy, and AMP-activated protein kinase (AMPK)-Unc-51 like autophagy activating kinase 1 (ULK1) signaling in cells with excess DRAM1. Thus, by promoting organelle contact between lysosomes and the ER, DRAM1 modulates ER structure and function and cell survival under stress. Our results suggest that DRAM1 as a lysosomal protein performs diverse roles in cellular homeostasis and stress response. These findings may have significant implications for our understanding of the role of the p53/DRAM1 axis in human diseases, from cancer to neurodegenerative diseases.
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Affiliation(s)
- Xiying Wang
- Department of Psychiatry, The Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing210029, China
| | - Ji Geng
- Department of Pathology, Stanford University School of Medicine, Stanford, CA94305
| | - Suman Rimal
- Department of Pathology, Stanford University School of Medicine, Stanford, CA94305
| | - Yuxiu Sui
- Department of Psychiatry, The Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing210029, China
| | - Jie Pan
- Department of Pathology, Stanford University School of Medicine, Stanford, CA94305
| | - Zhenghong Qin
- Institute of Health Technology, Global Institute of Software Technology, Suzhou215163, China
- Department of Pharmacology and Laboratory of Aging and Nervous Diseases, School of Pharmaceutical Sciences, Soochow University, Suzhou215123, China
| | - Bingwei Lu
- Department of Pathology, Stanford University School of Medicine, Stanford, CA94305
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5
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Caminos E, López-López S, Martinez-Galan JR. Selective Assembly of TRPC Channels in the Rat Retina during Photoreceptor Degeneration. Int J Mol Sci 2024; 25:7251. [PMID: 39000357 PMCID: PMC11242081 DOI: 10.3390/ijms25137251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
Transient receptor potential canonical (TRPC) channels are calcium channels with diverse expression profiles and physiological implications in the retina. Neurons and glial cells of rat retinas with photoreceptor degeneration caused by retinitis pigmentosa (RP) exhibit basal calcium levels that are above those detected in healthy retinas. Inner retinal cells are the last to degenerate and are responsible for maintaining the activity of the visual cortex, even after complete loss of photoreceptors. We considered the possibility that TRPC1 and TRPC5 channels might be associated with both the high calcium levels and the delay in inner retinal degeneration. TRPC1 is known to mediate protective effects in neurodegenerative processes while TRPC5 promotes cell death. In order to comprehend the implications of these channels in RP, the co-localization and subsequent physical interaction between TRPC1 and TRPC5 in healthy retina (Sprague-Dawley rats) and degenerating (P23H-1, a model of RP) retina were detected by immunofluorescence and proximity ligation assays. There was an overlapping signal in the innermost retina of all animals where TRPC1 and TRPC5 physically interacted. This interaction increased significantly as photoreceptor loss progressed. Both channels function as TRPC1/5 heteromers in the healthy and damaged retina, with a marked function of TRPC1 in response to retinal degenerative mechanisms. Furthermore, our findings support that TRPC5 channels also function in partnership with STIM1 in Müller and retinal ganglion cells. These results suggest that an increase in TRPC1/5 heteromers may contribute to the slowing of the degeneration of the inner retina during the outer retinal degeneration.
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Affiliation(s)
- Elena Caminos
- Department of Medical Science, Medical School of Albacete, Instituto de Biomedicina (IB-UCLM), University of Castilla-La Mancha, 02008 Albacete, Spain
| | - Susana López-López
- Department of Medical Science, Medical School of Albacete, Instituto de Biomedicina (IB-UCLM), University of Castilla-La Mancha, 02008 Albacete, Spain
- Consejo Superior de Investigaciones Científicas, and Research Unit, Complejo Hospitalario Universitario de Albacete, 02008 Albacete, Spain
| | - Juan R Martinez-Galan
- Department of Medical Science, Medical School of Albacete, Instituto de Biomedicina (IB-UCLM), University of Castilla-La Mancha, 02008 Albacete, Spain
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Wang J, Zhao J, Zhao K, Wu S, Chen X, Hu W. The Role of Calcium and Iron Homeostasis in Parkinson's Disease. Brain Sci 2024; 14:88. [PMID: 38248303 PMCID: PMC10813814 DOI: 10.3390/brainsci14010088] [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: 12/11/2023] [Revised: 01/04/2024] [Accepted: 01/09/2024] [Indexed: 01/23/2024] Open
Abstract
Calcium and iron are essential elements that regulate many important processes of eukaryotic cells. Failure to maintain homeostasis of calcium and iron causes cell dysfunction or even death. PD (Parkinson's disease) is the second most common neurological disorder in humans, for which there are currently no viable treatment options or effective strategies to cure and delay progression. Pathological hallmarks of PD, such as dopaminergic neuronal death and intracellular α-synuclein deposition, are closely involved in perturbations of iron and calcium homeostasis and accumulation. Here, we summarize the mechanisms by which Ca2+ signaling influences or promotes PD progression and the main mechanisms involved in ferroptosis in Parkinson's disease. Understanding the mechanisms by which calcium and iron imbalances contribute to the progression of this disease is critical to developing effective treatments to combat this devastating neurological disorder.
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Affiliation(s)
- Ji Wang
- School of Chinese Materia Medica & Yunnan Key Laboratory of Southern Medicine Utilization, Yunnan University of Chinese Medicine, Kunming 650500, China;
- School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China; (J.Z.); (K.Z.); (S.W.)
| | - Jindong Zhao
- School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China; (J.Z.); (K.Z.); (S.W.)
| | - Kunying Zhao
- School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China; (J.Z.); (K.Z.); (S.W.)
| | - Shangpeng Wu
- School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China; (J.Z.); (K.Z.); (S.W.)
| | - Xinglong Chen
- School of Chinese Materia Medica & Yunnan Key Laboratory of Southern Medicine Utilization, Yunnan University of Chinese Medicine, Kunming 650500, China;
| | - Weiyan Hu
- School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China; (J.Z.); (K.Z.); (S.W.)
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Geng X, Zou Y, Huang T, Li S, Pang A, Yu H. Electroacupuncture Improves Neuronal Damage and Mitochondrial Dysfunction Through the TRPC1 and SIRT1/AMPK Signaling Pathways to Alleviate Parkinson's Disease in Mice. J Mol Neurosci 2024; 74:5. [PMID: 38189854 DOI: 10.1007/s12031-023-02186-z] [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: 09/01/2023] [Accepted: 11/27/2023] [Indexed: 01/09/2024]
Abstract
Parkinson's disease (PD) is a neurodegenerative disease that mainly manifests as cognitive decline and motor dysfunction, the treatment of which is still a major challenge in the clinical field. Acupuncture therapy has been shown in many studies to enhance the body's own immunity and disease resistance. This study mainly discusses the specific mechanism underlying electroacupuncture intervention in improving PD. Male C57BL/6 mice were intraperitoneally injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce a mouse PD model, and the chorea trembling control area of the head of PD mice was treated by electroacupuncture. Western blotting was used to detect the expression of related proteins in mouse pathological samples; TUNEL measured neuronal apoptosis levels; Nissl staining observed neuronal damage; immunofluorescence and immunohistochemistry were used to detect the expression of Iba-1, TH, and α-syn in substantia nigra denser (SN). The expression levels of oxidative stress factors and inflammatory factors were measured by kits. Flow cytometry measured mitochondrial membrane potential and Ca2+ levels. MPTP intraperitoneal injection induced an increase in inflammatory factors in PD mice and promoted the oxidative stress response, and the inflammatory response was alleviated after electroacupuncture treatment. Electroacupuncture intervention effectively alters the decrease in oxidative stress levels and alleviates neuronal damage in PD mice. Electroacupuncture improves mitochondrial dysfunction induced by MPTP in PD mice by activating the SIRT1/AMPK signaling pathway. We also confirmed that knocking down TRPC1 can inhibit the SIRT1/AMPK signaling pathway, weaken the Ca2+ content in mouse neuronal tissue, and promote cell apoptosis. Electroacupuncture improves neuronal damage and alleviates PD in mice through the TRPC1 and SIRT1/AMPK signaling pathways. In addition, electroacupuncture therapy can improve MPTP-induced mitochondrial dysfunction in PD mice and alleviate the PD process.
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Affiliation(s)
- Xin Geng
- The Second Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
- Yunnan Provincial Clinical Research Center for Neurological Disease, Kunming, 650032, Yunnan, China
| | - Yanghong Zou
- The Second Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
- Yunnan Provincial Clinical Research Center for Neurological Disease, Kunming, 650032, Yunnan, China
| | - Tao Huang
- The Second Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
- Yunnan Provincial Clinical Research Center for Neurological Disease, Kunming, 650032, Yunnan, China
| | - Shipeng Li
- The Second Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
- Yunnan Provincial Clinical Research Center for Neurological Disease, Kunming, 650032, Yunnan, China
| | - Ailan Pang
- Yunnan Provincial Clinical Research Center for Neurological Disease, Kunming, 650032, Yunnan, China
- Department of Neurology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
| | - Hualin Yu
- The Second Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China.
- Yunnan Provincial Clinical Research Center for Neurological Disease, Kunming, 650032, Yunnan, China.
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Quan W, Wang Y, Chen YH, Shao Q, Gong YZ, Hu JW, Liu WH, Wu ZJ, Wang J, Ma SB, Li XQ. Screening of rosmarinic acid from Salvia miltiorrhizae acting on the novel target TRPC1 based on the 'homology modelling-virtual screening-molecular docking-affinity assay-activity evaluation' method. PHARMACEUTICAL BIOLOGY 2023; 61:155-164. [PMID: 36604840 PMCID: PMC9828776 DOI: 10.1080/13880209.2022.2160769] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 11/14/2022] [Accepted: 12/15/2022] [Indexed: 06/17/2023]
Abstract
CONTEXT Salvia miltiorrhizae Bunge (Lamiaceae) is a traditional Chinese medicine (TCM) for the treatment of 'thoracic obstruction'. Transient receptor potential canonical channel 1 (TRPC1) is a important target for myocardial injury treatment. OBJECTIVE This work screens the active component acting on TRPC1 from Salvia miltiorrhizae. MATERIALS AND METHODS TCM Systems Pharmacology Database and Analysis Platform (TCMSP) was used to retrieve Salvia miltiorrhiza compounds for preliminary screening by referring to Lipinski's rule of five. Then, the compound group was comprehensively scored by AutoDock Vina based on TRPC1 protein. Surface plasmon resonance (SPR) was used to determine the affinity of the optimal compound to TRPC1 protein. Western blot assay was carried out to observe the effect of the optimal compound on TRPC1 protein expression in HL-1 cells, and Fura-2/AM detection was carried out to observe the effect of the optimal compound on calcium influx in HEK293 cells. RESULTS Twenty compounds with relatively good characteristic parameters were determined from 202 compounds of Salvia miltiorrhiza. Rosmarinic acid (RosA) was obtained based on the molecular docking scoring function. RosA had a high binding affinity to TRPC1 protein (KD value = 1.27 µM). RosA (50 μM) could reduce the protein levels (417.1%) of TRPC1 after oxygen-glucose deprivation/reperfusion (OGD/R) in HL-1 cells and it could inhibit TRPC1-mediated Ca2+ influx injury (0.07 ΔRatio340/380) in HEK293 cells. DISCUSSION AND CONCLUSIONS We obtained the potential active component RosA acting on TRPC1 from Salvia miltiorrhizae, and we speculate that RosA may be a promising clinical candidate for myocardial injury therapy.
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Affiliation(s)
- Wei Quan
- Department of Pharmacy, Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, China
- Department of Pharmacology, School of Pharmacy, Air Force Medical University, Xi’an, China
| | - Yuan Wang
- Department of Neurosurgery, Wuhan No.1 Hospital, Wuhan, China
| | - Yu-han Chen
- Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Qing Shao
- Xi’an Mental Health Center, School of Medicine, Xi’an Jiaotong University, Xi’an, China
| | - Yang-ze Gong
- Xi’an Mental Health Center, School of Medicine, Xi’an Jiaotong University, Xi’an, China
| | - Jie-wen Hu
- Xi’an Mental Health Center, School of Medicine, Xi’an Jiaotong University, Xi’an, China
| | - Wei-hai Liu
- Department of Pharmacy, Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, China
| | - Zi-jun Wu
- Department of Pharmacy, Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, China
| | - Jie Wang
- Department of Pharmacy, Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, China
| | - Shan-bo Ma
- Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Xiao-qiang Li
- Department of Pharmacology, School of Pharmacy, Air Force Medical University, Xi’an, China
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Akan T, Aydın Y, Korkmaz OT, Ulupınar E, Saydam F. The Effects of Carvacrol on Transient Receptor Potential (TRP) Channels in an Animal Model of Parkinson's Disease. Neurotox Res 2023; 41:660-669. [PMID: 37452911 DOI: 10.1007/s12640-023-00660-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 06/23/2023] [Accepted: 07/07/2023] [Indexed: 07/18/2023]
Abstract
In this study, we aimed to investigate the effects of carvacrol (CA), a widely used phytochemical having anti-oxidant and neuroprotective effects, on transient receptor potential (TRP) channels in an animal model of Parkinson's disease (PD). A total of 64 adult male Spraque-Dawley rats were divided into four groups: sham-operated, PD animal model (unilateral intrastriatal injections of 6-hydroxydopamine (6-OHDA), 6 µg/µl), PD + vehicle (dimethyl sulfoxide (DMSO)) treatment, and PD + CA treatment (10 mg/kg, every other day, for 14 days). Half of the brain samples of substantia nigra pars compacta (SNpc) and striatum (CPu) were collected for immunohistochemistry and the remaining half were used for molecular analyses. CA treatment significantly increased the density of dopaminergic neurons immunolabeled with tyrosine hydroxylase and transient receptor potential canonical 1 (TRPC1) channel in the SNpc of PD animals. In contrast, the density of astrocytes immunolabeled with glial fibrillary acetic acid and transient receptor potential ankyrin 1 (TRPA1) channel significantly decreased following CA treatment in the CPu of PD animals. RT-PCR and western blot analyses showed that 6-OHDA administration significantly reduced TRPA1 and TPRPC1 mRNA expression and protein levels in both SNpc and CPu. CA treatment significantly upregulated TRPA1 expression in PD group, while TRPC1 levels did not display an alteration. Based on this data it was concluded that CA treatment might protect the number of dopaminergic neurons by reducing the reactive astrogliosis and modulating the expression of TRP channels in both neurons and astrocytes in an animal model of PD.
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Affiliation(s)
- Tülay Akan
- Department of Physiology, Faculty of Medicine, Afyonkarahisar Health Sciences University, Zafer Sağlık Külliyesi B Blok, Dörtyol Mah, 2078 Sk, No. 3, 03030, Afyonkarahisar, Turkey.
| | - Yasemin Aydın
- Department of Physiology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - Orhan Tansel Korkmaz
- Department of Physiology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - Emel Ulupınar
- Department of Anatomy, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - Faruk Saydam
- Department of Medical Biology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey
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Caminos E, Murillo-Martínez M, García-Belando M, Cabanes-Sanchís JJ, Martinez-Galan JR. Robust expression of the TRPC1 channel associated with photoreceptor loss in the rat retina. Exp Eye Res 2023; 236:109655. [PMID: 37722585 DOI: 10.1016/j.exer.2023.109655] [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: 05/02/2023] [Revised: 07/11/2023] [Accepted: 09/14/2023] [Indexed: 09/20/2023]
Abstract
Baseline intracellular calcium levels are significantly higher in neuronal and glial cells of rat retinas with retinitis pigmentosa (RP). Although this situation could initiate multiple detrimental pathways that lead to cell death, we considered the possibility of TRPC1 being involved in maintaining calcium homeostasis in the retina by acting as a component of store-operated calcium (SOC) channels with special relevance during photoreceptor degeneration. In this study, we examined by Western blot the expression of TRPC1 in healthy control rat retinas (Sprague-Dawley, SD) and retinas with RP (P23H-1 rats). We also analyzed its specific cellular distribution by immunofluorescence to recognize changes during neurodegeneration and to determine whether its presence is consistent with high basal calcium levels and cellular survival in degenerating retinas. We found that TRPC1 immunostaining was widely distributed across the retina in both rat strains, SD and P23H, and its expression levels significantly increased in the retinas with advanced degeneration compared to the age-control SD rats. In the outer retina, TRPC1 immunoreactivity was distributed in pigment epithelium cells, the photoreceptor inner segments of older animals, and the outer plexiform layer. In the inner retina, TRPC1 labeling was detected in horizontal cells, specific somata of bipolar and amacrine cells, and cellular processes in all the strata of the inner plexiform layer. Somata and processes were also highly immunoreactive in the ganglion cell layer and astrocytes in the nerve fiber layer in all animals. In the P23H rat retinas, the TRPC1 distribution pattern changed according to advancing photoreceptor degeneration and the gliosis reaction, with TRPC1 immunoreactive Müller cells mainly in advanced stages of disease. The cellular TRPC1 immunoreactivity found in this work suggests different mechanisms of activation of these channels depending on the cell type. Furthermore, the results support the idea that photoreceptor loss due to RP is associated with robust TRPC1 protein expression in the rat inner retina and raise the possibility of TRPC1 channels contributing to maintain high basal calcium levels during neurodegeneration and/or maintenance processes of the inner retina.
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Affiliation(s)
- Elena Caminos
- University of Castilla-La Mancha, Department of Medical Science, Medical School of Albacete, Instituto de Investigación en Discapacidades Neurológicas (IDINE), Albacete, Spain.
| | - Marina Murillo-Martínez
- University of Castilla-La Mancha, Department of Medical Science, Medical School of Albacete, Instituto de Investigación en Discapacidades Neurológicas (IDINE), Albacete, Spain.
| | - María García-Belando
- University of Castilla-La Mancha, Department of Medical Science, Medical School of Albacete, Instituto de Investigación en Discapacidades Neurológicas (IDINE), Albacete, Spain.
| | - José Julio Cabanes-Sanchís
- University of Castilla-La Mancha, Department of Medical Science, Medical School of Albacete, Instituto de Investigación en Discapacidades Neurológicas (IDINE), Albacete, Spain.
| | - Juan R Martinez-Galan
- University of Castilla-La Mancha, Department of Medical Science, Medical School of Albacete, Instituto de Investigación en Discapacidades Neurológicas (IDINE), Albacete, Spain.
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11
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Rather MA, Khan A, Wang L, Jahan S, Rehman MU, Makeen HA, Mohan S. TRP channels: Role in neurodegenerative diseases and therapeutic targets. Heliyon 2023; 9:e16910. [PMID: 37332910 PMCID: PMC10272313 DOI: 10.1016/j.heliyon.2023.e16910] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 04/09/2023] [Accepted: 05/31/2023] [Indexed: 06/20/2023] Open
Abstract
TRP (Transient receptor potential) channels are integral membrane proteins consisting of a superfamily of cation channels that allow permeability of both monovalent and divalent cations. TRP channels are subdivided into six subfamilies: TRPC, TRPV, TRPM, TRPP, TRPML, and TRPA, and are expressed in almost every cell and tissue. TRPs play an instrumental role in the regulation of various physiological processes. TRP channels are extensively represented in brain tissues and are present in both prokaryotes and eukaryotes, exhibiting responses to several mechanisms, including physical, chemical, and thermal stimuli. TRP channels are involved in the perturbation of Ca2+ homeostasis in intracellular calcium stores, both in neuronal and non-neuronal cells, and its discrepancy leads to several neuronal disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). TRPs participate in neurite outgrowth, receptor signaling, and excitotoxic cell death in the central nervous system. Understanding the mechanism of TRP channels in neurodegenerative diseases may extend to developing novel therapies. Thus, this review articulates TRP channels' physiological and pathological role in exploring new therapeutic interventions in neurodegenerative diseases.
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Affiliation(s)
- Mashoque Ahmad Rather
- Department of Molecular Pharmacology & Physiology, Bryd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, United States
| | - Andleeb Khan
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Lianchun Wang
- Department of Molecular Pharmacology & Physiology, Bryd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, United States
| | - Sadaf Jahan
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al Majma'ah, 11952, Saudi Arabia
| | - Muneeb U. Rehman
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Hafiz A. Makeen
- Pharmacy Practice Research Unit, Department of Pharmacy Practice, College of Pharmacy, Jazan University, 45142, Saudi Arabia
| | - Syam Mohan
- Substance Abuse and Toxicology Research Centre, Jazan University, Jazan, Saudi Arabia
- School of Health Sciences, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India
- Center for Transdisciplinary Research, Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, India
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12
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Filippini L, Ortner NJ, Kaserer T, Striessnig J. Ca v 1.3-selective inhibitors of voltage-gated L-type Ca 2+ channels: Fact or (still) fiction? Br J Pharmacol 2023; 180:1289-1303. [PMID: 36788128 PMCID: PMC10953394 DOI: 10.1111/bph.16060] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/17/2022] [Accepted: 01/29/2023] [Indexed: 02/16/2023] Open
Abstract
Voltage-gated L-type Ca2+ -channels (LTCCs) are the target of Ca2+ -channel blockers (CCBs), which are in clinical use for the evidence-based treatment of hypertension and angina. Their cardiovascular effects are largely mediated by the Cav 1.2-subtype. However, based on our current understanding of their physiological and pathophysiological roles, Cav 1.3 LTCCs also appear as attractive drug targets for the therapy of various diseases, including treatment-resistant hypertension, spasticity after spinal cord injury and neuroprotection in Parkinson's disease. Since CCBs inhibit both Cav 1.2 and Cav 1.3, Cav 1.3-selective inhibitors would be valuable tools to validate the therapeutic potential of Cav 1.3 channel inhibition in preclinical models. Despite a number of publications reporting the discovery of Cav 1.3-selective blockers, their selectivity remains controversial. We conclude that at present no pharmacological tools exist that are suitable to confirm or refute a role of Cav 1.3 channels in cellular responses. We also suggest essential criteria for a small molecule to be considered Cav 1.3-selective.
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Affiliation(s)
- Ludovica Filippini
- Department of Pharmacology and Toxicology and Center of Molecular BiosciencesUniversity of InnsbruckInnsbruckAustria
- Department of Pharmaceutical Chemistry, Institute of PharmacyUniversity of InnsbruckInnsbruckAustria
| | - Nadine J. Ortner
- Department of Pharmacology and Toxicology and Center of Molecular BiosciencesUniversity of InnsbruckInnsbruckAustria
| | - Teresa Kaserer
- Department of Pharmaceutical Chemistry, Institute of PharmacyUniversity of InnsbruckInnsbruckAustria
| | - Jörg Striessnig
- Department of Pharmacology and Toxicology and Center of Molecular BiosciencesUniversity of InnsbruckInnsbruckAustria
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13
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Bouron A. Neuronal Store-Operated Calcium Channels. Mol Neurobiol 2023:10.1007/s12035-023-03352-5. [PMID: 37118324 DOI: 10.1007/s12035-023-03352-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 04/13/2023] [Indexed: 04/30/2023]
Abstract
The endoplasmic reticulum (ER) is the major intracellular calcium (Ca2+) storage compartment in eukaryotic cells. In most instances, the mobilization of Ca2+ from this store is followed by a delayed and sustained uptake of Ca2+ through Ca2+-permeable channels of the cell surface named store-operated Ca2+ channels (SOCCs). This gives rise to a store-operated Ca2+ entry (SOCE) that has been thoroughly investigated in electrically non-excitable cells where it is the principal regulated Ca2+ entry pathway. The existence of this Ca2+ route in neurons has long been a matter of debate. However, a growing body of experimental evidence indicates that the recruitment of Ca2+ from neuronal ER Ca2+ stores generates a SOCE. The present review summarizes the main studies supporting the presence of a depletion-dependent Ca2+ entry in neurons. It also addresses the question of the molecular composition of neuronal SOCCs, their expression, pharmacological properties, as well as their physiological relevance.
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Affiliation(s)
- Alexandre Bouron
- Université Grenoble Alpes, CNRS, CEA, Inserm UA13 BGE, 38000, Grenoble, France.
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14
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Zhang YY, Li XS, Ren KD, Peng J, Luo XJ. Restoration of metal homeostasis: a potential strategy against neurodegenerative diseases. Ageing Res Rev 2023; 87:101931. [PMID: 37031723 DOI: 10.1016/j.arr.2023.101931] [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: 01/31/2023] [Revised: 04/04/2023] [Accepted: 04/06/2023] [Indexed: 04/11/2023]
Abstract
Metal homeostasis is critical to normal neurophysiological activity. Metal ions are involved in the development, metabolism, redox and neurotransmitter transmission of the central nervous system (CNS). Thus, disturbance of homeostasis (such as metal deficiency or excess) can result in serious consequences, including neurooxidative stress, excitotoxicity, neuroinflammation, and nerve cell death. The uptake, transport and metabolism of metal ions are highly regulated by ion channels. There is growing evidence that metal ion disorders and/or the dysfunction of ion channels contribute to the progression of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Therefore, metal homeostasis-related signaling pathways are emerging as promising therapeutic targets for diverse neurological diseases. This review summarizes recent advances in the studies regarding the physiological and pathophysiological functions of metal ions and their channels, as well as their role in neurodegenerative diseases. In addition, currently available metal ion modulators and in vivo quantitative metal ion imaging methods are also discussed. Current work provides certain recommendations based on literatures and in-depth reflections to improve neurodegenerative diseases. Future studies should turn to crosstalk and interactions between different metal ions and their channels. Concomitant pharmacological interventions for two or more metal signaling pathways may offer clinical advantages in treating the neurodegenerative diseases.
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Affiliation(s)
- Yi-Yue Zhang
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Xi-Sheng Li
- Department of Laboratory Medicine, The Third Xiangya Hospital of Central South University, Changsha 410013，China
| | - Kai-Di Ren
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Jun Peng
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
| | - Xiu-Ju Luo
- Department of Laboratory Medicine, The Third Xiangya Hospital of Central South University, Changsha 410013，China.
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15
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Park J, Jang KM, Park KK. Effects of Apamin on MPP +-Induced Calcium Overload and Neurotoxicity by Targeting CaMKII/ERK/p65/STAT3 Signaling Pathways in Dopaminergic Neuronal Cells. Int J Mol Sci 2022; 23:15255. [PMID: 36499581 PMCID: PMC9736188 DOI: 10.3390/ijms232315255] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/19/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022] Open
Abstract
Parkinson's disease (PD), a neurodegenerative disorder, is characterized by the loss of dopaminergic (DA) neurons. The pathogenesis of PD is associated with several factors including oxidative stress, inflammation, and mitochondrial dysfunction. Ca2+ signaling plays a vital role in neuronal signaling and altered Ca2+ homeostasis has been implicated in many neuronal diseases including PD. Recently, we reported that apamin (APM), a selective antagonist of the small-conductivity Ca2+-activated K+ (SK) channel, suppresses neuroinflammatory response. However, the mechanism(s) underlying the vulnerability of DA neurons were not fully understood. In this study, we investigated whether APM affected 1-methyl-4-phenyl pyridinium (MPP+)-mediated neurotoxicity in SH-SY5Y cells and rat embryo primary mesencephalic neurons. We found that APM decreased Ca2+ overload arising from MPP+-induced neurotoxicity response through downregulating the level of CaMKII, phosphorylation of ERK, and translocation of nuclear factor NFκB/signal transducer and activator of transcription (STAT)3. Furthermore, we showed that the correlation of MPP+-mediated Ca2+ overload and ERK/NFκB/STAT3 in the neurotoxicity responses, and dopaminergic neuronal cells loss, was verified through inhibitors. Our findings showed that APM might prevent loss of DA neurons via inhibition of Ca2+-overload-mediated signaling pathway and provide insights regarding the potential use of APM in treating neurodegenerative diseases.
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Affiliation(s)
- Jihyun Park
- Department of Pathology, College of Medicine, Catholic University of Daegu, Daegu 42472, Republic of Korea
| | - Kyung Mi Jang
- Department of Pediatrics, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
| | - Kwan-Kyu Park
- Department of Pathology, College of Medicine, Catholic University of Daegu, Daegu 42472, Republic of Korea
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16
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Qiu J, Bosch MA, Stincic TL, Hunker AC, Zweifel LS, Rønnekleiv OK, Kelly MJ. CRISPR/SaCas9 mutagenesis of stromal interaction molecule 1 in proopiomelanocortin neurons increases glutamatergic excitability and protects against diet-induced obesity. Mol Metab 2022; 66:101645. [PMID: 36442744 PMCID: PMC9727646 DOI: 10.1016/j.molmet.2022.101645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/09/2022] [Accepted: 11/22/2022] [Indexed: 11/26/2022] Open
Abstract
OBJECTIVE Proopiomelanocortin (POMC) neurons are the key anorexigenic hypothalamic neuron for integrating metabolic cues to generate the appropriate output for maintaining energy homeostasis and express the requisite channels as a perfect synaptic integrator in this role. Similar to the metabolic hormones leptin and insulin, glutamate also excites POMC neurons via group I metabotropic glutamate receptors (mGluR1 and 5, mGluR1/5) that activate Transient Receptor Potential Canonical (TRPC 5) Channels to cause depolarization. A key modulator of TRPC 5 channel activity is stromal interaction molecule 1 (STIM1), which is involved in recruitment of TRPC 5 channels from receptor-operated to store-operated calcium entry following depletion of calcium from the endoplasmic reticulum. METHODS We used a single adeno-associated viral (AAV) vector containing a recombinase-dependent Staphylococcus aureus Cas9 (SaCas) and a single guide RNA (sgRNA) to mutate Stim1 in POMCCre neurons in male mice, verified by qPCR of Stim1 mRNA expression in single POMC neurons. Whole-cell patch clamp experiments were conducted to validate the effects of Stim1 mutagenesis. Body weight and food intake were measured in male mice to assess disruptions in energy balance. RESULTS Reduced Stim1 expression augmented the efficacy of the mGluR1/5 agonist 3, 5-Dihydroxyphenylglycine (DHPG) to depolarize POMC neurons via a Gαq-coupled signaling pathway, which is an essential part of excitatory glutamatergic input in regulating energy homeostasis. The TRPC 5 channel blockers HC070 and Pico145 antagonized the excitatory effects of DHPG. As proof of principle, mutagenesis of Stim1 in POMC neurons reduced food intake, attenuated weight gain, reduced body fat and fat pad mass in mice fed a high fat diet. CONCLUSIONS Using CRISPR technology we have uncovered a critical role of STIM1 in modulating glutamatergic activation of TRPC 5 channels in POMC neurons, which ultimately is important for maintaining energy balance.
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Affiliation(s)
- Jian Qiu
- Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA,Corresponding author.Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA
| | - Martha A. Bosch
- Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA
| | - Todd L. Stincic
- Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA
| | - Avery C. Hunker
- Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA
| | - Larry S. Zweifel
- Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA,Department of Pharmacology, University of Washington, Seattle, WA 98195, USA
| | - Oline K. Rønnekleiv
- Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA,Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR 97006, USA
| | - Martin J. Kelly
- Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA,Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR 97006, USA,Corresponding author.Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA
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17
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Jawaid S, Herring AI, Getsy PM, Lewis SJ, Watanabe M, Kolesova H. Differential immunostaining patterns of transient receptor potential (TRP) ion channels in the rat nodose ganglion. J Anat 2022; 241:230-244. [PMID: 35396708 PMCID: PMC9296033 DOI: 10.1111/joa.13656] [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: 07/09/2021] [Revised: 01/26/2022] [Accepted: 03/07/2022] [Indexed: 11/27/2022] Open
Abstract
Vagal afferents regulate numerous physiological functions including arterial blood pressure, heart rate, breathing, and nociception. Cell bodies of vagal afferents reside in the inferior vagal (nodose) ganglia and their stimulation by various means is being considered as a way to regulate cardiorespiratory responses and control pain sensations. Stimulation of the nodose by exposure to infrared light is recently being considered as a precise way to elicit responses. These responses would likely involve the activity of temperature-sensitive membrane-bound channels. While papers have been published to track the expression of these transient receptor potential ion channels (TRPs), further studies are warranted to determine the in situ expression of the endogenous TRP proteins in the nodose ganglia to fully understand their pattern of expression, subcellular locations, and functions in this animal model. TRP ion channels are a superfamily of Na+ /Ca2+ -channels whose members are temperature- and/or mechano-sensitive and therefore represent a potential set of proteins that will be activated directly or indirectly by infrared light. Here, we report the spatial localization of six TRP channels, TRPV1, TRPV4, TRPM3, TRPM8, TRPA1, and TRPC1, from nodose ganglia taken from juvenile male Sprague-Dawley rats. The channels were detected using immunohistology with fluorescent tags on cryosections and imaged using confocal microscopy. All six TRP channels were detected with different levels of intensity in neuronal cell bodies and some were also detected in axonal fibers and blood vessels. The TRP receptors differed in their prevalence, in their patterns of expression, and in subcellular expression/localization. More specifically, TRPV1, TRPV4, TRPA1, TRPM8, TRPC1, and TRPM3 were found in vagal afferent cell bodies with a wide range of immunostaining intensity from neuron to neuron. Immunostaining for TRPV1, TRPV4, and TRPA1 appeared as fine particles scattered throughout the cytoplasm of the cell body. Intense TRPV1 immunostaining was also evident in a subset of axonal fibers. TRPM8 and TRPC1 were expressed in courser particles suggesting different subcellular compartments than for TRPV1. The localization of TRPM3 differed markedly from the other TRP channels with an immunostaining pattern that was localized to the periphery of a subset of cell bodies, whereas a scattering or no immunostaining was detected within the bulk of the cytoplasm. TRPV4 and TRPC1 were also expressed on the walls of blood vessels. The finding that all six TRP channels (representing four subfamilies) were present in the nodose ganglia provides the basis for studies designed to understand the roles of these channels in sensory transmission within vagal afferent fibers and in the responses elicited by exposure of nodose ganglia to infrared light and other stimuli. Depending on the location and functionality of the TRP channels, they may regulate the flux of Na+ /Ca2+ -across the membranes of cell bodies and axons of sensory afferents, efferent (motor) fibers coursing through the ganglia, and in vascular smooth muscle.
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Affiliation(s)
- Safdar Jawaid
- Divisions of Pediatric CardiologyCase Western Reserve University School of MedicineClevelandOHUSA
| | - Amanda I. Herring
- Divisions of Pediatric CardiologyCase Western Reserve University School of MedicineClevelandOHUSA
| | - Paulina M. Getsy
- Pediatric Pulmonology, Department of PediatricsCase Western Reserve University School of MedicineClevelandOHUSA
| | - Stephen J. Lewis
- Pediatric Pulmonology, Department of PediatricsCase Western Reserve University School of MedicineClevelandOHUSA
| | - Michiko Watanabe
- Divisions of Pediatric CardiologyCase Western Reserve University School of MedicineClevelandOHUSA
| | - Hana Kolesova
- Department of Anatomy, First Faculty of MedicineCharles UniversityPragueCzech Republic
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18
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Kong W, Zhu D, Luo R, Yu S, Ju H. Framework-promoted charge transfer for highly selective photoelectrochemical biosensing of dopamine. Biosens Bioelectron 2022; 211:114369. [PMID: 35594626 DOI: 10.1016/j.bios.2022.114369] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 05/04/2022] [Accepted: 05/10/2022] [Indexed: 11/16/2022]
Abstract
Traditional photoelectrochemical (PEC) systems with inorganic semiconductors as photoactive materials generally involve effortless recombination of electron-hole pairs, which greatly limit the detection sensitivity. The arrangement of multiple components with tunable bandgaps provides an effective way to accelerate charge transfer. In this work, a framework material with adjustable structure was used to promote the charge transfer in the PEC process. The framework was constructed with 9,10-di(p-carboxyphenyl)anthracene (DPA) ligands as the light collector to coordinate with Zn2+ nodes, which formed an electronegative metal-organic framework (ZnMOF), and showed good conductivity and PEC performance due to the π-π stacking of DPA and the intrareticular charge transfer. Based on the band and charge matching of dopamine (DA) with ZnMOF, the ZnMOF modified electrode as a biosensor showed excellent PEC response to DA with good selectivity, thus realized sensitive detection of DA ranging from 0.03 to 10 μM with a detection limit of 17.7 nM. The biosensor could be used to monitor the release of DA from PC12 cells and evaluate the stimulation of K+ to DA release. The conductive framework material provided an approach to develop highly selective sensing platform for trace bioanalysis.
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Affiliation(s)
- Weisu Kong
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, PR China
| | - Da Zhu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, PR China
| | - Rengan Luo
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, PR China
| | - Siqi Yu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, PR China
| | - Huangxian Ju
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, PR China.
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Collins HE, Zhang D, Chatham JC. STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases. FRONTIERS IN AGING 2022; 3:876785. [PMID: 35821821 PMCID: PMC9261457 DOI: 10.3389/fragi.2022.876785] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 03/30/2022] [Indexed: 01/19/2023]
Abstract
Tight spatiotemporal regulation of intracellular Ca2+ plays a critical role in regulating diverse cellular functions including cell survival, metabolism, and transcription. As a result, eukaryotic cells have developed a wide variety of mechanisms for controlling Ca2+ influx and efflux across the plasma membrane as well as Ca2+ release and uptake from intracellular stores. The STIM and Orai protein families comprising of STIM1, STIM2, Orai1, Orai2, and Orai3, are evolutionarily highly conserved proteins that are core components of all mammalian Ca2+ signaling systems. STIM1 and Orai1 are considered key players in the regulation of Store Operated Calcium Entry (SOCE), where release of Ca2+ from intracellular stores such as the Endoplasmic/Sarcoplasmic reticulum (ER/SR) triggers Ca2+ influx across the plasma membrane. SOCE, which has been widely characterized in non-excitable cells, plays a central role in Ca2+-dependent transcriptional regulation. In addition to their role in Ca2+ signaling, STIM1 and Orai1 have been shown to contribute to the regulation of metabolism and mitochondrial function. STIM and Orai proteins are also subject to redox modifications, which influence their activities. Considering their ubiquitous expression, there has been increasing interest in the roles of STIM and Orai proteins in excitable cells such as neurons and myocytes. While controversy remains as to the importance of SOCE in excitable cells, STIM1 and Orai1 are essential for cellular homeostasis and their disruption is linked to various diseases associated with aging such as cardiovascular disease and neurodegeneration. The recent identification of splice variants for most STIM and Orai isoforms while complicating our understanding of their function, may also provide insight into some of the current contradictions on their roles. Therefore, the goal of this review is to describe our current understanding of the molecular regulation of STIM and Orai proteins and their roles in normal physiology and diseases of aging, with a particular focus on heart disease and neurodegeneration.
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Affiliation(s)
- Helen E. Collins
- Division of Environmental Medicine, Department of Medicine, University of Louisville, Louisville, KY, United States
| | - Dingguo Zhang
- Division of Molecular and Cellular Pathology, Department of PathologyUniversity of Alabama at Birmingham, Birmingham, AL, United States
| | - John C. Chatham
- Division of Molecular and Cellular Pathology, Department of PathologyUniversity of Alabama at Birmingham, Birmingham, AL, United States,*Correspondence: John C. Chatham,
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20
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Store-operated Ca2+ entry regulates neuronal gene expression and function. Curr Opin Neurobiol 2022; 73:102520. [DOI: 10.1016/j.conb.2022.01.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 01/19/2022] [Accepted: 01/23/2022] [Indexed: 12/21/2022]
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21
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Deletion of Stim1 in Hypothalamic Arcuate Nucleus Kiss1 Neurons Potentiates Synchronous GCaMP Activity and Protects against Diet-Induced Obesity. J Neurosci 2021; 41:9688-9701. [PMID: 34654752 DOI: 10.1523/jneurosci.0622-21.2021] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 06/29/2021] [Accepted: 10/07/2021] [Indexed: 12/17/2022] Open
Abstract
Kisspeptin (Kiss1) neurons are essential for reproduction, but their role in the control of energy balance and other homeostatic functions remains unclear. High-frequency firing of hypothalamic arcuate Kiss1 (Kiss1ARH) neurons releases kisspeptin into the median eminence, and neurokinin B (NKB) and dynorphin onto neighboring Kiss1ARH neurons to generate a slow EPSP mediated by TRPC5 channels that entrains intermittent, synchronous firing of Kiss1ARH neurons. High-frequency optogenetic stimulation of Kiss1ARH neurons also releases glutamate to excite the anorexigenic proopiomelanocortin (POMC) neurons and inhibit the orexigenic neuropeptide Y/agouti-related peptide (AgRP) neurons via metabotropic glutamate receptors. At the molecular level, the endoplasmic reticulum (ER) calcium-sensing protein stromal interaction molecule 1 (STIM1) is critically involved in the regulation of neuronal Ca2+ signaling and neuronal excitability through its interaction with plasma membrane (PM) calcium (e.g., TRPC) channels. Therefore, we hypothesized that deletion of Stim1 in Kiss1ARH neurons would increase neuronal excitability and their synchronous firing, which ultimately would affect energy homeostasis. Using optogenetics in combination with whole-cell recording and GCaMP6 imaging in slices, we discovered that deletion of Stim1 in Kiss1 neurons significantly increased the amplitude and duration of the slow EPSP and augmented synchronous [Ca2+]i oscillations in Kiss1ARH neurons. Deletion of Stim1 in Kiss1ARH neurons amplified the actions of NKB and protected ovariectomized female mice from developing obesity and glucose intolerance with high-fat dieting (HFD). Therefore, STIM1 appears to play a critical role in regulating synchronous firing of Kiss1ARH neurons, which ultimately affects the coordination between energy homeostasis and reproduction.SIGNIFICANCE STATEMENT Hypothalamic arcuate kisspeptin (Kiss1ARH) neurons are essential for stimulating the pulsatile release of gonadotropin-releasing hormone (GnRH) and maintaining fertility. However, Kiss1ARH neurons appear to be a key player in coordinating energy balance with reproduction. The regulation of calcium channels and hence calcium signaling is critically dependent on the endoplasmic reticulum (ER) calcium-sensing protein stromal interaction molecule 1 (STIM1), which interacts with the plasma membrane (PM) calcium channels. We have conditionally deleted Stim1 in Kiss1ARH neurons and found that it significantly increased the excitability of Kiss1ARH neurons and protected ovariectomized female mice from developing obesity and glucose intolerance with high-fat dieting (HFD).
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22
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Ahamad N, Sun Y, Nascimento Da Conceicao V, Xavier Paul Ezhilan CRD, Natarajan M, Singh BB. Differential activation of Ca 2+ influx channels modulate stem cell potency, their proliferation/viability and tissue regeneration. NPJ Regen Med 2021; 6:67. [PMID: 34671058 PMCID: PMC8528841 DOI: 10.1038/s41536-021-00180-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 09/29/2021] [Indexed: 11/10/2022] Open
Abstract
Stem cells have indefinite self-renewable capability; however, factors that modulate their pluripotency/function are not fully identified. Here we show that store-dependent Ca2+ entry is essential for modulating the function of bone marrow-derived mesenchymal stem cells (MSCs). Increasing external Ca2+ modulated cell cycle progression that was critical for MSCs survival. Additionally, Ca2+ was critical for stem proliferation, its differentiation, and maintaining stem cell potential. Ca2+ channel characterization, including gene silencing, showed two distinct Ca2+ entry channels (through Orai1/TRPC1 or via Orai3) that differentially regulate the proliferation and viability of MSCs. Importantly, NFκB translocation, but not JNK/ERK into the nucleus, was observed upon store depletion, which was blocked by the addition of Ca2+ channel inhibitors. Radiation lead to a decrease in saliva secretion, decrease in acinar cell number, and enlarged ducts were observed, which were restored by the transplantation of stem cells that were propagated in higher Ca2+. Finally radiation showed a decrese in TRPC1 expression along with a decrese in AQP5, which was again restored upon MSC tranplantation. Together these results suggest that Ca2+ entry is essential for stem cell function that could be critical for regenerative medicine.
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Affiliation(s)
- Naseem Ahamad
- Department of Periodontics, School of Dentistry, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Yuyang Sun
- Department of Periodontics, School of Dentistry, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | | | - Caroline R D Xavier Paul Ezhilan
- Department of Pathology and Laboratory Medicine, School of Medicine, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Mohan Natarajan
- Department of Pathology and Laboratory Medicine, School of Medicine, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Brij B Singh
- Department of Periodontics, School of Dentistry, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
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Plasma Membrane and Organellar Targets of STIM1 for Intracellular Calcium Handling in Health and Neurodegenerative Diseases. Cells 2021; 10:cells10102518. [PMID: 34685498 PMCID: PMC8533710 DOI: 10.3390/cells10102518] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/14/2021] [Accepted: 09/21/2021] [Indexed: 01/08/2023] Open
Abstract
Located at the level of the endoplasmic reticulum (ER) membrane, stromal interacting molecule 1 (STIM1) undergoes a complex conformational rearrangement after depletion of ER luminal Ca2+. Then, STIM1 translocates into discrete ER-plasma membrane (PM) junctions where it directly interacts with and activates plasma membrane Orai1 channels to refill ER with Ca2+. Furthermore, Ca2+ entry due to Orai1/STIM1 interaction may induce canonical transient receptor potential channel 1 (TRPC1) translocation to the plasma membrane, where it is activated by STIM1. All these events give rise to store-operated calcium entry (SOCE). Besides the main pathway underlying SOCE, which mainly involves Orai1 and TRPC1 activation, STIM1 modulates many other plasma membrane proteins in order to potentiate the influxof Ca2+. Furthermore, it is now clear that STIM1 may inhibit Ca2+ currents mediated by L-type Ca2+ channels. Interestingly, STIM1 also interacts with some intracellular channels and transporters, including nuclear and lysosomal ionic proteins, thus orchestrating organellar Ca2+ homeostasis. STIM1 and its partners/effectors are significantly modulated in diverse acute and chronic neurodegenerative conditions. This highlights the importance of further disclosing their cellular functions as they might represent promising molecular targets for neuroprotection.
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Calcium Signaling Regulates Autophagy and Apoptosis. Cells 2021; 10:cells10082125. [PMID: 34440894 PMCID: PMC8394685 DOI: 10.3390/cells10082125] [Citation(s) in RCA: 132] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/10/2021] [Accepted: 08/17/2021] [Indexed: 02/07/2023] Open
Abstract
Calcium (Ca2+) functions as a second messenger that is critical in regulating fundamental physiological functions such as cell growth/development, cell survival, neuronal development and/or the maintenance of cellular functions. The coordination among various proteins/pumps/Ca2+ channels and Ca2+ storage in various organelles is critical in maintaining cytosolic Ca2+ levels that provide the spatial resolution needed for cellular homeostasis. An important regulatory aspect of Ca2+ homeostasis is a store operated Ca2+ entry (SOCE) mechanism that is activated by the depletion of Ca2+ from internal ER stores and has gained much attention for influencing functions in both excitable and non-excitable cells. Ca2+ has been shown to regulate opposing functions such as autophagy, that promote cell survival; on the other hand, Ca2+ also regulates programmed cell death processes such as apoptosis. The functional significance of the TRP/Orai channels has been elaborately studied; however, information on how they can modulate opposing functions and modulate function in excitable and non-excitable cells is limited. Importantly, perturbations in SOCE have been implicated in a spectrum of pathological neurodegenerative conditions. The critical role of autophagy machinery in the pathogenesis of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, would presumably unveil avenues for plausible therapeutic interventions for these diseases. We thus review the role of SOCE-regulated Ca2+ signaling in modulating these diverse functions in stem cell, immune regulation and neuromodulation.
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25
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Zhang X, Deng R, Zhang S, Deng J, Jia JJ, Sun B, Zhou X, Bai J. Thioredoxin-1 regulates calcium homeostasis in MPP + /MPTP-induced Parkinson's disease models. Eur J Neurosci 2021; 54:4827-4837. [PMID: 34132424 DOI: 10.1111/ejn.15355] [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: 02/26/2021] [Revised: 06/04/2021] [Accepted: 06/12/2021] [Indexed: 11/30/2022]
Abstract
Disturbance in calcium (Ca2+ ) homeostasis has been involved in a variety of neuropathological conditions including Parkinson's disease (PD). The Ca2+ channel, transient receptor potential channel 1 (TRPC1), plays a protective role in regulating entry of Ca2+ activated by store depletion of Ca2+ in endoplasmic reticulum (ER). We have showed that thioredoxin-1 (Trx-1) plays a role in suppressing ER stress in PD. However, whether Trx-1 regulates TRPC1 expression in PD is still unknown. In the present study, we demonstrated that treatment of 1-methyl-4-phenylpyridinum ion (MPP+ ) significantly reduced the expression of TRPC1 in PC12 cells, which was restored by Trx-1 overexpression, and further decreased significantly by Trx-1 siRNA. Moreover, we found that Ca2+ entered into the cells was decreased by MPP+ in PC 12 cells, which was restored by Trx-1 overexpression, and further decreased by Trx-1 siRNA. MPP+ significantly increased calcium-dependent cysteine protease calpain1 expression in PC12 cells, which was suppressed by Trx-1 overexpression. Calpain1 expression was increased by Trx-1 siRNA or SKF96365, an inhibitor of TRPC1. Moreover, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) decreased TRPC1 expression in the substantia nigra pars compacta region (SNpc), which was restored in mice overexpressing Trx-1, and further decreased in mice of knockdown Trx-1. Inversely, the expression of calpain1 was increased by MPTP, which was suppressed in mice overexpressing Trx-1, and further increased in mice of knockdown Trx-1. In conclusion, Trx-1 regulates the Ca2+ entry through regulating TRPC1 expression after treatment of MPP+ /MPTP.
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Affiliation(s)
- Xianwen Zhang
- Laboratory of molecular neurobiology, Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Ruhua Deng
- Laboratory of molecular neurobiology, Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Se Zhang
- Laboratory of molecular neurobiology, Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Juan Deng
- Laboratory of molecular neurobiology, Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Jing Jing Jia
- Laboratory of molecular neurobiology, Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Bo Sun
- Laboratory of molecular neurobiology, Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Xiaoshuang Zhou
- Laboratory of molecular neurobiology, Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Jie Bai
- Laboratory of molecular neurobiology, Medical Faculty, Kunming University of Science and Technology, Kunming, China
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The gating pore blocker 1-(2,4-xylyl)guanidinium selectively inhibits pacemaking of midbrain dopaminergic neurons. Neuropharmacology 2021; 197:108722. [PMID: 34273387 DOI: 10.1016/j.neuropharm.2021.108722] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 07/08/2021] [Accepted: 07/13/2021] [Indexed: 11/22/2022]
Abstract
Although several ionic mechanisms are known to control rate and regularity of the slow pacemaker in dopamine (DA) neurons, the core mechanism of pacing is controversial. Here we tested the hypothesis that pacemaking of SNc DA neurons is enabled by an unconventional conductance. We found that 1-(2,4-xylyl)guanidinium (XG), an established blocker of gating pore currents, selectively inhibits pacemaking of DA neurons. The compound inhibited all slow pacemaking DA neurons that were tested, both in the substantia nigra pars compacta, and in the ventral tegmental area. Interestingly, bursting behavior was not affected by XG. Furthermore, the drug did not affect fast pacemaking of GABAergic neurons from substantia nigra pars reticulata neurons or slow pacemaking of noradrenergic neurons. In DA neurons, current-clamp analysis revealed that XG did not appear to affect ion channels involved in the action potential. Its inhibitory effect persisted during blockade of all ion channels previously suggested to contribute to pacemaking. RNA sequencing and voltage-clamp recordings yielded no evidence for a gating pore current to underlie the conductance. However, we could isolate a small subthreshold XG-sensitive current, which was carried by both Na+ and Cl- ions. Although the molecular target of XG remains to be defined, these observations represent a step towards understanding pacemaking in DA neurons.
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27
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Chauhan A, Sharma A, Tripathi JK, Sun Y, Sukumran P, Singh BB, Mishra BB, Sharma J. Helminth derived factors inhibit neutrophil extracellular trap formation and inflammation in bacterial peritonitis. Sci Rep 2021; 11:12718. [PMID: 34135384 PMCID: PMC8209178 DOI: 10.1038/s41598-021-92001-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 06/03/2021] [Indexed: 01/18/2023] Open
Abstract
Despite their protective antimicrobial function, neutrophil extracellular traps (NETs) have been implicated in propagation of inflammatory responses in several disease conditions including sepsis. Highly diffusible exogenous ROS produced under such inflammatory conditions, can induce exuberant NETs, thus making inhibition of NETs desirable in inflammatory diseases. Here we report that helminth parasite excretory/secretory factors termed as parasitic ligands (PL) inhibit ROS-induced NETs by blocking the activation of nonselective calcium permeable channel Transient Receptor Potential Melastatin 2 (TRPM2). Therapeutic implication of PL mediated blockage of NET formation was tested in preclinical model of septic peritonitis, where PL treatment regulated neutrophil cell death modalities including NET formation and mitigated neutrophil mediated inflammatory response. This translated into improved survival and reduced systemic and local bacterial load in infected mice. Overall, our results posit PL as an important biological regulator of neutrophil functions with implications to a variety of inflammatory diseases including peritonitis.
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Affiliation(s)
- Arun Chauhan
- Department of Biomedical Sciences, The University of North Dakota School of Medicine and Health Sciences, 1301 N Columbia Road, Grand Forks, ND, 58202-9037, USA
| | - Atul Sharma
- Department of Biomedical Sciences, The University of North Dakota School of Medicine and Health Sciences, 1301 N Columbia Road, Grand Forks, ND, 58202-9037, USA
- Department of Critical Care, Division of Anesthesiology, Critical Care and Pain Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 110, Houston, TX, 77030-4009, USA
| | - Jitendra K Tripathi
- Department of Biomedical Sciences, The University of North Dakota School of Medicine and Health Sciences, 1301 N Columbia Road, Grand Forks, ND, 58202-9037, USA
- Department of Geriatrics, The University of North Dakota School of Medicine and Health Sciences, 1301 N Columbia Road, Grand Forks, ND, 58202-9037, USA
| | - Yuyang Sun
- Department of Periodontics, School of Dentistry, University of Texas Health Science Center, San Antonio, TX, USA
| | - Pramod Sukumran
- Department of Periodontics, School of Dentistry, University of Texas Health Science Center, San Antonio, TX, USA
| | - Brij B Singh
- Department of Periodontics, School of Dentistry, University of Texas Health Science Center, San Antonio, TX, USA
| | - Bibhuti B Mishra
- Department of Biomedical Sciences, The University of North Dakota School of Medicine and Health Sciences, 1301 N Columbia Road, Grand Forks, ND, 58202-9037, USA.
| | - Jyotika Sharma
- Department of Biomedical Sciences, The University of North Dakota School of Medicine and Health Sciences, 1301 N Columbia Road, Grand Forks, ND, 58202-9037, USA.
- Department of Critical Care, Division of Anesthesiology, Critical Care and Pain Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 110, Houston, TX, 77030-4009, USA.
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28
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Waites C, Qu X, Bartolini F. The synaptic life of microtubules. Curr Opin Neurobiol 2021; 69:113-123. [PMID: 33873059 DOI: 10.1016/j.conb.2021.03.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/03/2021] [Accepted: 03/08/2021] [Indexed: 12/21/2022]
Abstract
In neurons, control of microtubule dynamics is required for multiple homeostatic and regulated activities. Over the past few decades, a great deal has been learned about the role of the microtubule cytoskeleton in axonal and dendritic transport, with a broad impact on neuronal health and disease. However, significantly less attention has been paid to the importance of microtubule dynamics in directly regulating synaptic function. Here, we review emerging literature demonstrating that microtubules enter synapses and control central aspects of synaptic activity, including neurotransmitter release and synaptic plasticity. The pleiotropic effects caused by a dysfunctional synaptic microtubule cytoskeleton may thus represent a key point of vulnerability for neurons and a primary driver of neurological disease.
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Affiliation(s)
- Clarissa Waites
- Department of Neuroscience, Columbia University, 3227 Broadway, New York, NY 10027, USA
| | - Xiaoyi Qu
- Department of Pathology & Cell Biology, Columbia University Medical Center, 630 W. 168th Street, New York, NY 10032, USA
| | - Francesca Bartolini
- Department of Pathology & Cell Biology, Columbia University Medical Center, 630 W. 168th Street, New York, NY 10032, USA.
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29
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Lee K, Jo YY, Chung G, Jung JH, Kim YH, Park CK. Functional Importance of Transient Receptor Potential (TRP) Channels in Neurological Disorders. Front Cell Dev Biol 2021; 9:611773. [PMID: 33748103 PMCID: PMC7969799 DOI: 10.3389/fcell.2021.611773] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 02/09/2021] [Indexed: 12/11/2022] Open
Abstract
Transient receptor potential (TRP) channels are transmembrane protein complexes that play important roles in the physiology and pathophysiology of both the central nervous system (CNS) and the peripheral nerve system (PNS). TRP channels function as non-selective cation channels that are activated by several chemical, mechanical, and thermal stimuli as well as by pH, osmolarity, and several endogenous or exogenous ligands, second messengers, and signaling molecules. On the pathophysiological side, these channels have been shown to play essential roles in the reproductive system, kidney, pancreas, lung, bone, intestine, as well as in neuropathic pain in both the CNS and PNS. In this context, TRP channels have been implicated in several neurological disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and epilepsy. Herein, we focus on the latest involvement of TRP channels, with a special emphasis on the recently identified functional roles of TRP channels in neurological disorders related to the disruption in calcium ion homeostasis.
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Affiliation(s)
- Kihwan Lee
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon, South Korea
| | - Youn Yi Jo
- Department of Anesthesiology and Pain Medicine, Gil Medical Center, Gachon University, Incheon, South Korea
| | - Gehoon Chung
- Department of Oral Physiology and Program in Neurobiology, School of Dentistry, Seoul National University, Seoul, South Korea
| | - Jung Hoon Jung
- Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada
| | - Yong Ho Kim
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon, South Korea
| | - Chul-Kyu Park
- Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon, South Korea
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30
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Jeon J, Bu F, Sun G, Tian JB, Ting SM, Li J, Aronowski J, Birnbaumer L, Freichel M, Zhu MX. Contribution of TRPC Channels in Neuronal Excitotoxicity Associated With Neurodegenerative Disease and Ischemic Stroke. Front Cell Dev Biol 2021; 8:618663. [PMID: 33490083 PMCID: PMC7820370 DOI: 10.3389/fcell.2020.618663] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 12/11/2020] [Indexed: 12/12/2022] Open
Abstract
The seven canonical members of transient receptor potential (TRPC) proteins form cation channels that evoke membrane depolarization and intracellular calcium concentration ([Ca2+] i ) rise, which are not only important for regulating cell function but their deregulation can also lead to cell damage. Recent studies have implicated complex roles of TRPC channels in neurodegenerative diseases including ischemic stroke. Brain ischemia reduces oxygen and glucose supply to neurons, i.e., Oxygen and Glucose Deprivation (OGD), resulting in [Ca2+] i elevation, ion dyshomeostasis, and excitotoxicity, which are also common in many forms of neurodegenerative diseases. Although ionotropic glutamate receptors, e.g., N-methyl-D-aspartate receptors, are well established to play roles in excitotoxicity, the contribution of metabotropic glutamate receptors and their downstream effectors, i.e., TRPC channels, should not be neglected. Here, we summarize the current findings about contributions of TRPC channels in neurodegenerative diseases, with a focus on OGD-induced neuronal death and rodent models of cerebral ischemia/reperfusion. TRPC channels play both detrimental and protective roles to neurodegeneration depending on the TRPC subtype and specific pathological conditions involved. When illustrated the mechanisms by which TRPC channels are involved in neuronal survival or death seem differ greatly, implicating diverse and complex regulation. We provide our own data showing that TRPC1/C4/C5, especially TRPC4, may be generally detrimental in OGD and cerebral ischemia/reperfusion. We propose that although TRPC channels significantly contribute to ischemic neuronal death, detailed mechanisms and specific roles of TRPC subtypes in brain injury at different stages of ischemia/reperfusion and in different brain regions need to be carefully and systematically investigated.
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Affiliation(s)
- Jaepyo Jeon
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Fan Bu
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Guanghua Sun
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Jin-Bin Tian
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Shun-Ming Ting
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Jun Li
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Jaroslaw Aronowski
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Lutz Birnbaumer
- Institute for Biomedical Research (BIOMED UCA-CONICET), Buenos Aires, Argentina.,School of Medical Sciences, Catholic University of Argentina (UCA), Buenos Aires, Argentina.,Neurobiology Laboratory, National Institute of Environmental Health Sciences, Durham, NC, United States
| | - Marc Freichel
- Department of Pharmacology, Heidelberg University, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany
| | - Michael X Zhu
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
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31
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Serwach K, Gruszczynska-Biegala J. Target Molecules of STIM Proteins in the Central Nervous System. Front Mol Neurosci 2020; 13:617422. [PMID: 33424550 PMCID: PMC7786003 DOI: 10.3389/fnmol.2020.617422] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 12/02/2020] [Indexed: 12/16/2022] Open
Abstract
Stromal interaction molecules (STIMs), including STIM1 and STIM2, are single-pass transmembrane proteins that are located predominantly in the endoplasmic reticulum (ER). They serve as calcium ion (Ca2+) sensors within the ER. In the central nervous system (CNS), they are involved mainly in Orai-mediated store-operated Ca2+ entry (SOCE). The key molecular components of the SOCE pathway are well-characterized, but the molecular mechanisms that underlie the regulation of this pathway need further investigation. Numerous intracellular target proteins that are located in the plasma membrane, ER, cytoskeleton, and cytoplasm have been reported to play essential roles in concert with STIMs, such as conformational changes in STIMs, their translocation, the stabilization of their interactions with Orai, and the activation of other channels. The present review focuses on numerous regulators, such as Homer, SOCE-associated regulatory factor (SARAF), septin, synaptopodin, golli proteins, partner of STIM1 (POST), and transcription factors and proteasome inhibitors that regulate STIM-Orai interactions in the CNS. Further we describe novel roles of STIMs in mediating Ca2+ influx via other than Orai pathways, including TRPC channels, VGCCs, AMPA and NMDA receptors, and group I metabotropic glutamate receptors. This review also summarizes recent findings on additional molecular targets of STIM proteins including SERCA, IP3Rs, end-binding proteins (EB), presenilin, and CaMKII. Dysregulation of the SOCE-associated toolkit, including STIMs, contributes to the development of neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, and Huntington's disease), traumatic brain injury, epilepsy, and stroke. Emerging evidence points to the role of STIM proteins and several of their molecular effectors and regulators in neuronal and glial physiology and pathology, suggesting their potential application for future therapeutic strategies.
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Affiliation(s)
- Karolina Serwach
- Molecular Biology Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
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32
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Zhang I, Hu H. Store-Operated Calcium Channels in Physiological and Pathological States of the Nervous System. Front Cell Neurosci 2020; 14:600758. [PMID: 33328896 PMCID: PMC7732603 DOI: 10.3389/fncel.2020.600758] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 11/03/2020] [Indexed: 12/13/2022] Open
Abstract
Store-operated calcium channels (SOCs) are widely expressed in excitatory and non-excitatory cells where they mediate significant store-operated calcium entry (SOCE), an important pathway for calcium signaling throughout the body. While the activity of SOCs has been well studied in non-excitable cells, attention has turned to their role in neurons and glia in recent years. In particular, the role of SOCs in the nervous system has been extensively investigated, with links to their dysregulation found in a wide variety of neurological diseases from Alzheimer’s disease (AD) to pain. In this review, we provide an overview of their molecular components, expression, and physiological role in the nervous system and describe how the dysregulation of those roles could potentially lead to various neurological disorders. Although further studies are still needed to understand how SOCs are activated under physiological conditions and how they are linked to pathological states, growing evidence indicates that SOCs are important players in neurological disorders and could be potential new targets for therapies. While the role of SOCE in the nervous system continues to be multifaceted and controversial, the study of SOCs provides a potentially fruitful avenue into better understanding the nervous system and its pathologies.
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Affiliation(s)
- Isis Zhang
- Department of Anesthesiology, Rutgers New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United States
| | - Huijuan Hu
- Department of Anesthesiology, Rutgers New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United States
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33
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Vaidya B, Sharma SS. Transient Receptor Potential Channels as an Emerging Target for the Treatment of Parkinson's Disease: An Insight Into Role of Pharmacological Interventions. Front Cell Dev Biol 2020; 8:584513. [PMID: 33330461 PMCID: PMC7714790 DOI: 10.3389/fcell.2020.584513] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 10/30/2020] [Indexed: 12/21/2022] Open
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the symptoms of motor deficits and cognitive decline. There are a number of therapeutics available for the treatment of PD, but most of them suffer from serious side effects such as bradykinesia, dyskinesia and on-off effect. Therefore, despite the availability of these pharmacological agents, PD patients continue to have an inferior quality of life. This has warranted a need to look for alternate strategies and molecular targets. Recent evidence suggests the Transient Receptor Potential (TRP) channels could be a potential target for the management of motor and non-motor symptoms of PD. Though still in the preclinical stages, agents targeting these channels have shown immense potential in the attenuation of behavioral deficits and signaling pathways. In addition, these channels are known to be involved in the regulation of ionic homeostasis, which is disrupted in PD. Moreover, activation or inhibition of many of the TRP channels by calcium and oxidative stress has also raised the possibility of their paramount involvement in affecting the other molecular mechanisms associated with PD pathology. However, due to the paucity of information available and lack of specificity, none of these agents have gone into clinical trials for PD treatment. Considering their interaction with oxidative stress, apoptosis and excitotoxicity, TRP channels could be considered as a potential future target for the treatment of PD.
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Affiliation(s)
- Bhupesh Vaidya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, India
| | - Shyam Sunder Sharma
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, India
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34
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Sun Y, Nascimento Da Conceicao V, Ahamad N, Madesh M, Singh BB. Spatial localization of SOCE channels and its modulators regulate neuronal physiology and contributes to pathology. CURRENT OPINION IN PHYSIOLOGY 2020. [DOI: 10.1016/j.cophys.2020.07.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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35
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Ye J, Yin Y, Yin Y, Zhang H, Wan H, Wang L, Zuo Y, Gao D, Li M, Li J, Liu Y, Ke D, Wang J. Tau-induced upregulation of C/EBPβ-TRPC1-SOCE signaling aggravates tauopathies: A vicious cycle in Alzheimer neurodegeneration. Aging Cell 2020; 19:e13209. [PMID: 32815315 PMCID: PMC7511862 DOI: 10.1111/acel.13209] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 06/28/2020] [Accepted: 07/07/2020] [Indexed: 12/19/2022] Open
Abstract
Intracellular accumulating of the hyperphosphorylated tau plays a pivotal role in neurodegeneration of Alzheimer disease (AD), but the mechanisms underlying the gradually aggravated tau hyperphosphorylation remain elusive. Here, we show that increasing intracellular tau could upregulate mRNA and protein levels of TRPC1 (transient receptor potential channel 1) with an activated store‐operated calcium entry (SOCE), an increased intraneuronal steady‐state [Ca2+]i, an enhanced endoplasmic reticulum (ER) stress, an imbalanced protein kinases and phosphatase, and an aggravated tauopathy. Furthermore, overexpressing TRPC1 induced ER stress, kinases‐phosphatase imbalance, tau hyperphosphorylation and cognitive deficits in cultured neurons and mice, while pharmacological inhibiting or knockout TRPC1 attenuated the hTau‐induced deregulations in SOCE, ER homeostasis, kinases‐phosphatase balance, and tau phosphorylation level with improved synaptic and cognitive functions. Finally, an increased CCAAT‐enhancer‐binding protein (C/EBPβ) activity was observed in hTau‐overexpressing cells and the hippocampus of the AD patients, while downregulating C/EBPβ by siRNA abolished the hTau‐induced TRPC1 upregulation. These data reveal that increasing intracellular tau can upregulate C/EBPβ‐TRPC1‐SOCE signaling and thus disrupt phosphorylating system, which together aggravates tau pathologies leading to a chronic neurodegeneration.
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Affiliation(s)
- Jinwang Ye
- Key Laboratory of Ministry of Education of China for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Ying Yin
- Key Laboratory of Ministry of Education of China for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Yaling Yin
- Department of Physiology and Neurobiology School of Basic Medical Sciences Xinxiang Medical University Xinxiang China
| | - Huaqiu Zhang
- Department of Neurosurgery Key Laboratory of Ministry of Education of China for Neurological Disorders Tongji Hospital Huazhong University of Science and Technology Wuhan China
| | - Huali Wan
- Key Laboratory of Ministry of Education of China for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Lu Wang
- Department of Physiology and Neurobiology School of Basic Medical Sciences Xinxiang Medical University Xinxiang China
| | - Yue Zuo
- Department of Physiology and Neurobiology School of Basic Medical Sciences Xinxiang Medical University Xinxiang China
| | - Di Gao
- Key Laboratory of Ministry of Education of China for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Mengzhu Li
- Key Laboratory of Ministry of Education of China for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology Wuhan China
- Department of Neurosurgery The Central Hospital of Wuhan Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Jun Li
- Department of Neurosurgery The Central Hospital of Wuhan Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Yanchao Liu
- Key Laboratory of Ministry of Education of China for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Dan Ke
- Key Laboratory of Ministry of Education of China for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Jian‐Zhi Wang
- Key Laboratory of Ministry of Education of China for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology Wuhan China
- Co‐innovation Center of Neurodegeneration Nantong University Nantong China
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Duitama M, Vargas-López V, Casas Z, Albarracin SL, Sutachan JJ, Torres YP. TRP Channels Role in Pain Associated With Neurodegenerative Diseases. Front Neurosci 2020; 14:782. [PMID: 32848557 PMCID: PMC7417429 DOI: 10.3389/fnins.2020.00782] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 07/02/2020] [Indexed: 01/09/2023] Open
Abstract
Transient receptor potential (TRP) are cation channels expressed in both non-excitable and excitable cells from diverse tissues, including heart, lung, and brain. The TRP channel family includes 28 isoforms activated by physical and chemical stimuli, such as temperature, pH, osmotic pressure, and noxious stimuli. Recently, it has been shown that TRP channels are also directly or indirectly activated by reactive oxygen species. Oxidative stress plays an essential role in neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, and TRP channels are involved in the progression of those diseases by mechanisms involving changes in the crosstalk between Ca2+ regulation, oxidative stress, and production of inflammatory mediators. TRP channels involved in nociception include members of the TRPV, TRPM, TRPA, and TRPC subfamilies that transduce physical and chemical noxious stimuli. It has also been reported that pain is a complex issue in patients with Alzheimer's and Parkinson's diseases, and adequate management of pain in those conditions is still in discussion. TRPV1 has a role in neuroinflammation, a critical mechanism involved in neurodegeneration. Therefore, some studies have considered TRPV1 as a target for both pain treatment and neurodegenerative disorders. Thus, this review aimed to describe the TRP-dependent mechanism that can mediate pain sensation in neurodegenerative diseases and the therapeutic approach available to palliate pain and neurodegenerative symptoms throughout the regulation of these channels.
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Therapeutic potential of pharmacological agents targeting TRP channels in CNS disorders. Pharmacol Res 2020; 159:105026. [PMID: 32562815 DOI: 10.1016/j.phrs.2020.105026] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 05/21/2020] [Accepted: 06/11/2020] [Indexed: 02/07/2023]
Abstract
Central nervous system (CNS) disorders like Alzheimer's disease (AD), Parkinson disease (PD), stroke, epilepsy, depression, and bipolar disorder have a high impact on both medical and social problems due to the surge in their prevalence. All of these neuronal disorders share some common etiologies including disruption of Ca2+ homeostasis and accumulation of misfolded proteins. These misfolded proteins further disrupt the intracellular Ca2+ homeostasis by disrupting the activity of several ion channels including transient receptor potential (TRP) channels. TRP channel families include non-selective Ca2+ permeable channels, which act as cellular sensors activated by various physio-chemical stimuli, exogenous, and endogenous ligands responsible for maintaining the intracellular Ca2+ homeostasis. TRP channels are abundantly expressed in the neuronal cells and disturbance in their activity leads to various neuronal diseases. Under the pathological conditions when the activity of TRP channels is perturbed, there is a disruption of the neuronal homeostasis through increased inflammatory response, generation of reactive oxygen species, and mitochondrial dysfunction. Therefore, there is a potential of pharmacological interventions targeting TRP channels in CNS disorders. This review focuses on the role of TRP channels in neurological diseases; also, we have highlighted the current insights into the pharmacological modulators targeting TRP channels.
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Sun Y, Kamat A, Singh BB. Isoproterenol-Dependent Activation of TRPM7 Protects Against Neurotoxin-Induced Loss of Neuroblastoma Cells. Front Physiol 2020; 11:305. [PMID: 32390858 PMCID: PMC7193110 DOI: 10.3389/fphys.2020.00305] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 03/19/2020] [Indexed: 12/17/2022] Open
Abstract
Neuronal function and their survival depend on the activation of ion channels. Loss of ion channel function is known to induce neurodegenerative diseases such as Parkinson’s that exhibit loss of dopaminergic neurons; however, mechanisms that could limit neuronal loss are not yet fully identified. Our data suggest that neurotoxin-mediated loss of neuroblastoma SH-SY5Y cells is inhibited by the addition of β-adrenergic receptor (β-AR) agonist isoproterenol. The addition of isoproterenol to SHSY-5Y cells showed increased Mg2+ influx and cell survival in the presence of neurotoxin especially at higher concentration of isoproterenol. Importantly, isoproterenol potentiated transient receptor potential melastatin-7 (TRPM7) channel activation that leads to an increase in intracellular Mg2+ levels. The addition of 2APB, which is a known TRPM7 channel blocker, significantly decreased the TRPM7 function and inhibited isoproterenol-mediated protection against neurotoxins. Moreover, neurotoxins inhibited TRPM7 expression and function, but the restoration of TRPM7 expression increased neuroblastoma cell survival. In contrast, TRPM7 silencing increased cell loss, decreased Mg2+ homeostasis, and inhibited mitochondrial function. Moreover, isoproterenol treatment prevented neurotoxin-mediated loss of TRPM7 expression and inhibited Bax expression that induces cell survival. These effects were dependent on the neurotoxin-induced increase in oxidative stress, which inhibits TRPM7 expression and function. Together, our results suggest a positive role for β-AR in activating TRPM7 channels that regulate Mg2+ homeostasis and are essential for the survival of SH-SY5Y cells from neurotoxin.
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Affiliation(s)
- Yuyang Sun
- Department of Periodontics, School of Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.,Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Amrita Kamat
- Department of Periodontics, School of Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.,Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Brij B Singh
- Department of Periodontics, School of Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.,Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
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Maria-Ferreira D, de Oliveira NMT, da Silva LCM, Fernandes ES. Evidence of a Role for the TRPC Subfamily in Mediating Oxidative Stress in Parkinson's Disease. Front Physiol 2020; 11:332. [PMID: 32457638 PMCID: PMC7225354 DOI: 10.3389/fphys.2020.00332] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 03/23/2020] [Indexed: 12/20/2022] Open
Abstract
Parkinson's disease (PD) represents one of the most common multifactorial neurodegenerative disorders affecting the elderly population. It is associated with the aggregation of α-synuclein protein and the loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. The disease is mainly represented by motor symptoms, such as resting tremors, postural instability, rigidity, and bradykinesia, that develop slowly over time. Parkinson's disease can also manifest as disturbances in non-motor functions. Although the pathology of PD has not yet been fully understood, it has been suggested that the disruption of the cellular redox status may contribute to cellular oxidative stress and, thus, to cell death. The generation of reactive oxygen species and reactive nitrogen intermediates, as well as the dysfunction of dopamine metabolism, play important roles in the degeneration of dopaminergic neurons. In this context, the transient receptor potential channel canonical (TRPC) sub-family plays an important role in neuronal degeneration. Additionally, PD gene products, including DJ-1, SNCA, UCH-L1, PINK-1, and Parkin, also interfere with mitochondrial function leading to reactive oxygen species production and dopaminergic neuronal vulnerability to oxidative stress. Herein, we discuss the interplay between these various biochemical and molecular events that ultimately lead to dopaminergic signaling disruption, highlighting the recently identified roles of TRPC in PD.
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Affiliation(s)
- Daniele Maria-Ferreira
- Faculdades Pequeno Príncipe, Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Curitiba, Brazil
- Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Brazil
| | - Natalia Mulinari Turin de Oliveira
- Faculdades Pequeno Príncipe, Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Curitiba, Brazil
- Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Brazil
| | - Liziane Cristine Malaquias da Silva
- Faculdades Pequeno Príncipe, Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Curitiba, Brazil
- Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Brazil
| | - Elizabeth Soares Fernandes
- Faculdades Pequeno Príncipe, Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Curitiba, Brazil
- Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Brazil
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40
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Lou D, Wang J, Wang X. Single nucleotide polymorphisms in the non-coding region of STIM1 gene are associated with Parkinson disease risk in Chinese Han population. Medicine (Baltimore) 2020; 99:e19234. [PMID: 32118726 PMCID: PMC7478395 DOI: 10.1097/md.0000000000019234] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The stromal interaction molecule 1 (STIM1) gene contributes essentially to Ca transport, thus it is functionally related to neurodegenerative disorders. The objective of this study was to investigate the correlation between single nucleotide polymorphisms (SNP) in the non-coding region of STIM1 gene and the risk for Parkinson disease (PD) in a Chinese Han population.In a cohort composed of 300 PD patients and 300 healthy individuals from a Chinese Han population, we analyzed genotypes for five novel SNPs, rs7934581, rs3794050, rs1561876, rs3750994 and rs3750996 in the non-coding region of STIM1 gene. The levels of STIM1 protein in plasma of these subjects were also assessed by enzyme-linked immunosorbent assay (ELISA).We found that the SNPs of STIM1 gene rs7934581, rs3794050, rs1561876, and rs3750996 were associated with increased PD risk, while rs3750994 SNP was not. An increased risk of PD was observed in subjects with the TAAG and TGAG haplotypes of rs7934581, rs3794050, rs1561876, rs3750996. Moreover, PD risk was significantly elevated only in subjects with age ≥60 years or females who carry the STIM1 rs3794050 minor allele. There was a significant difference in plasma STIM1 protein levels between subjects with different genotypes of STIM1 rs7934581, rs3794050, rs1561876, and rs3750996.STIM1 gene rs7934581, rs3794050, rs1561876, rs3750996 SNPs are associated with increased PD risk, and its mechanism may be related to abnormal STIM1 gene expression.
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Affiliation(s)
- Danning Lou
- Department of Neurology, The Affiliated Hospital of Hangzhou Normal University
| | - Jun Wang
- Binjiang clinic, Zhejiang Chinese Medical University
| | - Xiaohang Wang
- Department of Neurology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
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41
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Gruszczynska-Biegala J, Strucinska K, Maciag F, Majewski L, Sladowska M, Kuznicki J. STIM Protein-NMDA2 Receptor Interaction Decreases NMDA-Dependent Calcium Levels in Cortical Neurons. Cells 2020; 9:E160. [PMID: 31936514 PMCID: PMC7017226 DOI: 10.3390/cells9010160] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 01/05/2020] [Accepted: 01/07/2020] [Indexed: 01/08/2023] Open
Abstract
Neuronal Store-Operated Ca2+ Entry (nSOCE) plays an essential role in refilling endoplasmic reticulum Ca2+ stores and is critical for Ca2+-dependent neuronal processes. SOCE sensors, STIM1 and STIM2, can activate Orai, TRP channels and AMPA receptors, and inhibit voltage-gated channels in the plasma membrane. However, the link between STIM, SOCE, and NMDA receptors, another key cellular entry point for Ca2+ contributing to synaptic plasticity and excitotoxicity, remains unclear. Using Ca2+ imaging, we demonstrated that thapsigargin-induced nSOCE was inhibited in rat cortical neurons following NMDAR inhibitors. Blocking nSOCE by its inhibitor SKF96365 enhanced NMDA-driven [Ca2+]i. Modulating STIM protein level through overexpression or shRNA inhibited or activated NMDA-evoked [Ca2+]i, respectively. Using proximity ligation assays, immunofluorescence, and co-immunoprecipitation methods, we discovered that thapsigargin-dependent effects required interactions between STIMs and the NMDAR2 subunits. Since STIMs modulate NMDAR-mediated Ca2+ levels, we propose targeting this mechanism as a novel therapeutic strategy against neuropathological conditions that feature NMDA-induced Ca2+ overload as a diagnostic criterion.
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Affiliation(s)
- Joanna Gruszczynska-Biegala
- Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology in Warsaw, 02-109 Warsaw, Poland; (K.S.); (F.M.); (L.M.); (M.S.); (J.K.)
- Molecular Biology Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, 02-106 Warsaw, Poland
| | - Klaudia Strucinska
- Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology in Warsaw, 02-109 Warsaw, Poland; (K.S.); (F.M.); (L.M.); (M.S.); (J.K.)
| | - Filip Maciag
- Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology in Warsaw, 02-109 Warsaw, Poland; (K.S.); (F.M.); (L.M.); (M.S.); (J.K.)
| | - Lukasz Majewski
- Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology in Warsaw, 02-109 Warsaw, Poland; (K.S.); (F.M.); (L.M.); (M.S.); (J.K.)
| | - Maria Sladowska
- Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology in Warsaw, 02-109 Warsaw, Poland; (K.S.); (F.M.); (L.M.); (M.S.); (J.K.)
| | - Jacek Kuznicki
- Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology in Warsaw, 02-109 Warsaw, Poland; (K.S.); (F.M.); (L.M.); (M.S.); (J.K.)
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Glaser T, Arnaud Sampaio VF, Lameu C, Ulrich H. Calcium signalling: A common target in neurological disorders and neurogenesis. Semin Cell Dev Biol 2019; 95:25-33. [DOI: 10.1016/j.semcdb.2018.12.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2018] [Revised: 12/03/2018] [Accepted: 12/03/2018] [Indexed: 12/20/2022]
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Morris J, Gonzales CB, De La Chapa JJ, Cabang AB, Fountzilas C, Patel M, Orozco S, Wargovich MJ. The Highly Pure Neem Leaf Extract, SCNE, Inhibits Tumorigenesis in Oral Squamous Cell Carcinoma via Disruption of Pro-tumor Inflammatory Cytokines and Cell Signaling. Front Oncol 2019; 9:890. [PMID: 31572681 PMCID: PMC6753233 DOI: 10.3389/fonc.2019.00890] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 08/27/2019] [Indexed: 12/23/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is a deadly disease that comprises 60% of all head and neck squamous cell cancers. The leaves of the Neem tree (Azadirachta indica) have been used in traditional Ayurvedic medicine for centuries to treat numerous oral maladies and are known to have significant anti-inflammatory properties. We hypothesize that a highly pure super critical CO2 Neem leaf extract (SCNE) prevents initiation and progression of OSCC via downregulation of intra-tumor pro-inflammatory pathways, which promote tumorigenesis. Hence, we investigated the anticancer effects of SCNE using in vitro and in vivo platforms. OSCC cell lines (SCC4, Cal27, and HSC3) were treated with SCNE while inflammation, proliferation, and migration were analyzed over time. SCNE treatment significantly inhibited OSCC cell proliferation and migration and reduced MMP activity in vitro, suggesting its potential to inhibit tumor growth and metastasis. The preventive effects of SCNE in ectopic xenograft and 4NQO-1 (4-Nitroquinoline-1-oxide) carcinogen-induced mouse models of OSCC were also evaluated. Indeed, xenografted nude mice showed significant reduction of OSCC tumor volumes. Likewise, SCNE significantly reduced the incidence of tongue dysplasia in the 4NQO-1 OSCC initiation model. In both OSCC animal models, SCNE significantly depressed circulating pro-cancer inflammatory cytokines (host and tumor-secreted) including NFkB, COX2, IL-1, IL-6, TNFα, and IFNγ. In addition, we demonstrate that SCNE downregulates STAT3 and AKT expression and activity in vitro. We also demonstrate that the primary active component, nimbolide (NIM), has significant anticancer activity in established OSCC xenografts. Lastly, we show that SCNE induces an M1 phenotype in tumor associated macrophages (TAMS) in vivo. Taken together, these data strongly support SCNE as means of preventing OSCC via downregulation of pro-cancer inflammatory cascades and NIM as a potential new therapy for existing OSCC.
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Affiliation(s)
- Jay Morris
- Department of Molecular Medicine, Long School of Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX, United States
| | - Cara B. Gonzales
- Department of Comprehensive Dentistry, University of Texas Health Science Center San Antonio, San Antonio, TX, United States
| | - Jorge J. De La Chapa
- Department of Comprehensive Dentistry, University of Texas Health Science Center San Antonio, San Antonio, TX, United States
| | - April B. Cabang
- Department of Molecular Medicine, Long School of Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX, United States
| | - Christos Fountzilas
- Department of Medicine, GI Medical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Mandakini Patel
- Department of Molecular Medicine, Long School of Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX, United States
| | - Stephanie Orozco
- Department of Molecular Medicine, Long School of Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX, United States
| | - Michael J. Wargovich
- Department of Molecular Medicine, Long School of Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX, United States
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Magnesium-Induced Cell Survival Is Dependent on TRPM7 Expression and Function. Mol Neurobiol 2019; 57:528-538. [PMID: 31392516 PMCID: PMC6968994 DOI: 10.1007/s12035-019-01713-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 07/18/2019] [Indexed: 12/17/2022]
Abstract
Mg2+ homeostasis is essential for cell survival and the loss of this regulation has been associated with many neurodegenerative diseases, including loss of dopaminergic neurons. Although the neurotoxin-mediated loss of dopaminergic neurons in Parkinson disease models is extensively studied, the ion channel(s) that regulate Mg2+ homeostasis and thus could prevent neuronal cell death is not yet identified. Here, we show that TRPM7 (transient receptor potential melastatin 7) is involved in regulating Mg2+ homeostasis in dopaminergic cells. Importantly, transient loss of TRPM7 decreased intracellular Mg2+ levels and decreased dopaminergic cells/neurons survival. We provide further evidence that both increases in extracellular Mg2+ or transiently increasing TRPM7 levels protected dopaminergic SH-SY5Y cells against neurotoxin-mediated cell death. Neurotoxin treatment significantly decreased TRPM7 levels in both SH-SY5Y cells and the substantia nigra pars compacta region of mice, along with a decrease in Mg2+ influx. Moreover, Mg2+ supplementation showed a concentration-dependent decrease in caspase-3 activity, an increase in cell survival, restored mitochondrial membrane potential, and increase TRPM7 levels in neurotoxin-treated cells. In contrast, transient silencing of TRPM7 inhibited the positive effect of Mg2+ supplementation in protecting against neurotoxins. Whereas, TRPM7 overexpression not only maintained Mg2+ homeostasis but also inhibited caspase 3 activity that induced cell survival. Overall, these results suggest a significant role of TRPM7 channels in Mg2+ homeostasis and the survival of neurotoxin-induced loss of dopaminergic cells.
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45
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Sather WA, Dittmer PJ. Regulation of voltage-gated calcium channels by the ER calcium sensor STIM1. Curr Opin Neurobiol 2019; 57:186-191. [PMID: 31260893 DOI: 10.1016/j.conb.2019.01.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 01/21/2019] [Indexed: 01/13/2023]
Abstract
The endoplasmic reticulum (ER) Ca2+ sensor STIM1, best-known for its essential role in triggering influx of extracellular Ca2+ via Ca2+-release-activated channels when ER stores become depleted, unexpectedly also regulates Ca2+ entry through voltage-gated Ca2+ channels. In response to a drop in ER luminal Ca2+ level, this ER membrane-spanning sensor can contact voltage-gated Ca2+ channels in the plasma membrane and thereby inhibit Ca2+ influx through them. This previously unappreciated, interaction between ER Ca2+ level and magnitude of Ca2+ influx via voltage-gated Ca2+ channels may turn out to powerfully impact Ca2+ signaling in excitable cells, including neurotransmitter release, structural and functional postsynaptic plasticity, and transcription factor translocation.
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Affiliation(s)
- William A Sather
- Department of Pharmacology, University of Colorado School of Medicine, 12800 E. 19th Avenue, Aurora, CO 80045, USA.
| | - Philip J Dittmer
- Department of Pharmacology, University of Colorado School of Medicine, 12800 E. 19th Avenue, Aurora, CO 80045, USA
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46
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Luo H, Han L, Xu J. Apelin/APJ system: A novel promising target for neurodegenerative diseases. J Cell Physiol 2019; 235:638-657. [DOI: 10.1002/jcp.29001] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Accepted: 06/06/2019] [Indexed: 12/17/2022]
Affiliation(s)
- Huaiqing Luo
- Department of Physiology Changsha Medical University Changsha Hunan China
- Department of Physiology, School of Basic Medical Science Central South University Changsha Hunan China
| | - Li Han
- Department of Physiology Changsha Medical University Changsha Hunan China
| | - Jin Xu
- School of Pharmaceutical Sciences Changsha Medical University Changsha Hunan China
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47
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Kim J, Ko J, Myeong J, Kwak M, Hong C, So I. TRPC1 as a negative regulator for TRPC4 and TRPC5 channels. Pflugers Arch 2019; 471:1045-1053. [PMID: 31222490 DOI: 10.1007/s00424-019-02289-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 05/17/2019] [Accepted: 06/04/2019] [Indexed: 12/12/2022]
Abstract
Transient receptor potential canonical (TRPC) channels are calcium permeable, non-selective cation channels with wide tissue-specific distribution. Among 7 TRPC channels, TRPC 1/4/5 and TRPC3/6/7 are subdivided based on amino acid sequence homology. TRPC4 and TRPC5 channels exhibit cationic current with homotetrameric form, but they also form heterotetrameric channel such as TRPC1/4 or TRPC1/5 once TRPC1 is incorporated. The expression of TRPC1 is ubiquitous whereas the expressions of TRPC4 and TRPC5 are rather focused in nervous system. With the help of conditional knock-out of TPRC1, 4 and/or 5 genes, TRPC channels made of these constituents are reported to be involved in various pathophysiological functions such as seizure, anxiety-like behaviour, fear, Huntington's disease, Parkinson's disease and many others. In heterologous expression system, many issues such as activation mechanism, stoichiometry and relative cation permeabilites of homomeric or heteromeric channels have been addressed. In this review, we discussed the role of TRPC1 channel per se in plasma membrane, role of TRPC1 in heterotetrameric conformation (TRPC1/4 or TRPC1/5) and relationship between TRPC1/4/5 channels, calcium influx and voltage-gated calcium channels.
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Affiliation(s)
- Jinsung Kim
- Department of Physiology, College of Medicine, Seoul National University, Seoul, South Korea
| | - Juyeon Ko
- Department of Physiology, College of Medicine, Seoul National University, Seoul, South Korea
| | - Jongyun Myeong
- Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA, USA
| | - Misun Kwak
- Department of Physiology, College of Medicine, Seoul National University, Seoul, South Korea
| | - Chansik Hong
- Department of Physiology, College of Medicine, Chosun University, Kwangju, South Korea
| | - Insuk So
- Department of Physiology, College of Medicine, Seoul National University, Seoul, South Korea.
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Serwach K, Gruszczynska-Biegala J. STIM Proteins and Glutamate Receptors in Neurons: Role in Neuronal Physiology and Neurodegenerative Diseases. Int J Mol Sci 2019; 20:ijms20092289. [PMID: 31075835 PMCID: PMC6539036 DOI: 10.3390/ijms20092289] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 04/17/2019] [Accepted: 04/30/2019] [Indexed: 12/13/2022] Open
Abstract
Neuronal calcium (Ca2+) influx has long been ascribed mainly to voltage-gated Ca2+ channels and glutamate receptor channels. Recent research has shown that it is also complemented by stromal interaction molecule (STIM) protein-mediated store-operated Ca2+ entry (SOCE). SOCE is described as Ca2+ flow into cells in response to the depletion of endoplasmic reticulum Ca2+ stores. The present review summarizes recent studies that indicate a relationship between neuronal SOCE that is mediated by STIM1 and STIM2 proteins and glutamate receptors under both physiological and pathological conditions, such as neurodegenerative disorders. We present evidence that the dysregulation of neuronal SOCE and glutamate receptor activity are hallmarks of acute neurodegenerative diseases (e.g., traumatic brain injury and cerebral ischemia) and chronic neurodegenerative diseases (e.g., Alzheimer's disease and Huntington's disease). Emerging evidence indicates a role for STIM proteins and glutamate receptors in neuronal physiology and pathology, making them potential therapeutic targets.
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Affiliation(s)
- Karolina Serwach
- Molecular Biology Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego Str., 02-106 Warsaw, Poland.
| | - Joanna Gruszczynska-Biegala
- Molecular Biology Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego Str., 02-106 Warsaw, Poland.
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Calcium Deregulation and Mitochondrial Bioenergetics in GDAP1-Related CMT Disease. Int J Mol Sci 2019; 20:ijms20020403. [PMID: 30669311 PMCID: PMC6359725 DOI: 10.3390/ijms20020403] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 01/11/2019] [Accepted: 01/12/2019] [Indexed: 12/17/2022] Open
Abstract
The pathology of Charcot-Marie-Tooth (CMT), a disease arising from mutations in different genes, has been associated with an impairment of mitochondrial dynamics and axonal biology of mitochondria. Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause several forms of CMT neuropathy, but the pathogenic mechanisms involved remain unclear. GDAP1 is an outer mitochondrial membrane protein highly expressed in neurons. It has been proposed to play a role in different aspects of mitochondrial physiology, including mitochondrial dynamics, oxidative stress processes, and mitochondrial transport along the axons. Disruption of the mitochondrial network in a neuroblastoma model of GDAP1-related CMT has been shown to decrease Ca2+ entry through the store-operated calcium entry (SOCE), which caused a failure in stimulation of mitochondrial respiration. In this review, we summarize the different functions proposed for GDAP1 and focus on the consequences for Ca2+ homeostasis and mitochondrial energy production linked to CMT disease caused by different GDAP1 mutations.
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Liss B, Striessnig J. The Potential of L-Type Calcium Channels as a Drug Target for Neuroprotective Therapy in Parkinson's Disease. Annu Rev Pharmacol Toxicol 2019; 59:263-289. [PMID: 30625283 DOI: 10.1146/annurev-pharmtox-010818-021214] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The motor symptoms of Parkinson's disease (PD) mainly arise from degeneration of dopamine neurons within the substantia nigra. As no disease-modifying PD therapies are available, and side effects limit long-term benefits of current symptomatic therapies, novel treatment approaches are needed. The ongoing phase III clinical study STEADY-PD is investigating the potential of the dihydropyridine isradipine, an L-type Ca2+ channel (LTCC) blocker, for neuroprotective PD therapy. Here we review the clinical and preclinical rationale for this trial and discuss potential reasons for the ambiguous outcomes of in vivo animal model studies that address PD-protective dihydropyridine effects. We summarize current views about the roles of Cav1.2 and Cav1.3 LTCC isoforms for substantia nigra neuron function, and their high vulnerability to degenerative stressors, and for PD pathophysiology. We discuss different dihydropyridine sensitivities of LTCC isoforms in view of their potential as drug targets for PD neuroprotection, and we conclude by considering how these aspects could guide further drug development.
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Affiliation(s)
- Birgit Liss
- Institut für Angewandte Physiologie, Universität Ulm, 89081 Ulm, Germany;
| | - Jörg Striessnig
- Abteilung Pharmakologie und Toxikologie, Institut für Pharmazie, and Center for Molecular Biosciences Innsbruck, Universität Innsbruck, A-6020 Innsbruck, Austria;
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