|
1
|
Meng MY, Paine LW, Sagnat D, Bello I, Oldroyd S, Javid F, Harper MT, Hockley JRF, St John Smith E, Owens RM, Alric L, Buscail E, Welsh F, Vergnolle N, Bulmer DC. TRPV4 stimulates colonic afferents through mucosal release of ATP and glutamate. Br J Pharmacol 2025; 182:1324-1340. [PMID: 39626870 DOI: 10.1111/bph.17408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 10/11/2024] [Accepted: 10/17/2024] [Indexed: 02/11/2025] Open
Abstract
BACKGROUND AND PURPOSE Abdominal pain is a leading cause of morbidity for people living with gastrointestinal disease. Whereas the transient receptor potential vanilloid 4 (TRPV4) ion channel has been implicated in the pathogenesis of abdominal pain, the relative paucity of TRPV4 expression in colon-projecting sensory neurons suggests that non-neuronal cells may contribute to TRPV4-mediated nociceptor stimulation. EXPERIMENTAL APPROACH Changes in murine colonic afferent activity were examined using ex vivo electrophysiology in tissues with the gut mucosa present or removed. ATP and glutamate release were measured by bioluminescence assays from human colon organoid cultures and mouse colon. Dorsal root ganglion sensory neuron activity was evaluated by Ca2+ imaging when cultured alone or co-cultured with colonic mucosa. KEY RESULTS Bath application of TRPV4 agonist GSK1016790A elicited a robust increase in murine colonic afferent activity, which was abolished by removing the gut mucosa. GSK1016790A promoted ATP and glutamate release from human colon organoid cultures and mouse colon. Inhibition of ATP degradation in mouse colon enhanced the afferent response to GSK1016790A. Pretreatment with purinoceptor or glutamate receptor antagonists attenuated and abolished the response to GSK1016790A when given alone or in combination, respectively. Sensory neurons co-cultured with colonic mucosal cells produced a marked increase in intracellular Ca2+ to GSK1016790A compared with neurons cultured alone. CONCLUSION AND IMPLICATIONS Our data indicate that mucosal release of ATP and glutamate is responsible for the stimulation of colonic afferents following TRPV4 activation. These findings highlight an opportunity to target the gut mucosa for the development of new visceral analgesics.
Collapse
Affiliation(s)
- Michelle Y Meng
- Department of Pharmacology, University of Cambridge, Cambridge, UK
| | - Luke W Paine
- Department of Pharmacology, University of Cambridge, Cambridge, UK
| | - David Sagnat
- IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Université Toulouse III-Paul Sabatier (UPS), Toulouse, France
| | - Ivana Bello
- IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Université Toulouse III-Paul Sabatier (UPS), Toulouse, France
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Sophie Oldroyd
- Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
| | - Farideh Javid
- Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield, UK
| | - Matthew T Harper
- Department of Pharmacology, University of Cambridge, Cambridge, UK
| | | | | | - Róisín M Owens
- Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
| | - Laurent Alric
- Internal Medicine Department of Digestive Disease, CHU Toulouse-Rangueil and Université de Toulouse, Université Toulouse III-Paul Sabatier (UPS), Toulouse, France
| | - Etienne Buscail
- IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Université Toulouse III-Paul Sabatier (UPS), Toulouse, France
- Department of Surgery, CHU Toulouse-Rangueil and Université de Toulouse, Université Toulouse III-Paul Sabatier (UPS), Toulouse, France
| | - Fraser Welsh
- BioPharmaceuticals R&D, AstraZeneca, Neuroscience, Cambridge, UK
| | - Nathalie Vergnolle
- IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Université Toulouse III-Paul Sabatier (UPS), Toulouse, France
- Department of Physiology and Pharmacology, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
| | - David C Bulmer
- Department of Pharmacology, University of Cambridge, Cambridge, UK
| |
Collapse
|
|
2
|
Dragoni S, Moccia F, Bootman MD. The Roles of Transient Receptor Potential (TRP) Channels Underlying Aberrant Calcium Signaling in Blood-Retinal Barrier Dysfunction. Cold Spring Harb Perspect Biol 2025; 17:a041763. [PMID: 39586624 PMCID: PMC11864113 DOI: 10.1101/cshperspect.a041763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2024]
Abstract
The inner blood-retinal barrier (iBRB) protects the retinal vasculature from the peripheral circulation. Endothelial cells (ECs) are the core component of the iBRB; their close apposition and linkage via tight junctions limit the passage of fluids, proteins, and cells from the bloodstream to the parenchyma. Dysfunction of the iBRB is a hallmark of many retinal disorders. Vascular endothelial growth factor (VEGF) has been identified as the primary driver leading to a dysfunctional iBRB, thereby becoming the main target for therapy. However, a complete understanding of the molecular mechanisms underlying iBRB dysfunction is elusive and alternative therapeutic targets remain unexplored. Calcium (Ca2+) is a universal intracellular messenger whose homeostasis and dynamics are dysregulated in many pathological disorders. Among the extensive components of the cellular Ca2+-signaling toolkit, cation-selective transient receptor potential (TRP) channels are broadly involved in cell physiology and disease and, therefore, are widely studied as possible targets for therapy. Albeit that TRP channels have been discovered in the photoreceptors of Drosophila and have been studied in the neuroretina, their presence and function in the iBRB have only recently emerged. Within this article, we discuss the structure and functions of the iBRB with a particular focus on Ca2+ signaling in retinal ECs and highlight the potential of TRP channels as new targets for retinal diseases.
Collapse
Affiliation(s)
- Silvia Dragoni
- Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom
| | - Francesco Moccia
- Department of Biology and Biotechnology "Lazzaro Spallanzani," University of Pavia, Pavia 27100, Italy
| | - Martin D Bootman
- School of Life, Health and Chemical Sciences, Faculty of Science, Technology, Engineering and Mathematics, The Open University, Milton Keynes MK7 6AA, United Kingdom
| |
Collapse
|
|
3
|
Chinigò G, Ruffinatti FA, Munaron L. The potential of TRP channels as new prognostic and therapeutic targets against prostate cancer progression. Biochim Biophys Acta Rev Cancer 2024; 1879:189226. [PMID: 39586480 DOI: 10.1016/j.bbcan.2024.189226] [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: 03/25/2024] [Revised: 10/28/2024] [Accepted: 11/21/2024] [Indexed: 11/27/2024]
Abstract
Prostate cancer (PCa) is the second deadliest cancer among men worldwide. Particularly critical is its development towards metastatic androgen-independent forms for which the current therapies are ineffective. Indeed, the 5-year relative survival for PCa drops dramatically to 34 % in the presence of metastases. The superfamily of Transient Receptor Potential (TRP) channels could answer the urgent request to identify new prognostic and therapeutic tools against metastatic PCa. Indeed, this class of ion channels revealed an appealing de-regulation during PCa development and its progression towards aggressive forms. Altered expression and/or functionality of several TRPs have been associated with the PCa metastatic cascade by significantly impacting tumor growth, invasiveness, and angiogenesis. In this review, we will dissect the contribution of TRP channels in such hallmarks of PCa and then discuss their applicability as new prognostic and therapeutic agents in the fight against metastatic PCa. In particular, the great potential of TRPM8, TRPV6, and TRPA1 in opening the way to new treatment perspectives will be highlighted.
Collapse
Affiliation(s)
- Giorgia Chinigò
- University of Turin, Department of Life Sciences and Systems Biology, via Accademia Albertina 13, 10123 Turin, Italy.
| | | | - Luca Munaron
- University of Turin, Department of Life Sciences and Systems Biology, via Accademia Albertina 13, 10123 Turin, Italy.
| |
Collapse
|
|
4
|
Schaller L, Gudermann T, Dietrich A. TRPV4 Mediates Alveolar Epithelial Barrier Integrity and Induces ADAM10-Driven E-Cadherin Shedding. Cells 2024; 13:1717. [PMID: 39451235 PMCID: PMC11506556 DOI: 10.3390/cells13201717] [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: 09/23/2024] [Revised: 10/11/2024] [Accepted: 10/15/2024] [Indexed: 10/26/2024] Open
Abstract
Transient receptor potential vanilloid 4 (TRPV4) channels have been associated with numerous pulmonary pathologies, including hypertension, asthma, and acute lung injury. However, their role in the alveolar epithelium remains unclear. We performed impedance-based resistance measurements in primary differentiated alveolar epithelial type I (AT1) cells from wild-type (WT) and TRPV4-deficient (TRPV4-/-) C57/BL6J mice to detect changes in AT1 barrier integrity upon TRPV4 activation. Both pharmacological (GSK1016790A) and a low pH-driven activation of TRPV4 were quantified, and the downstream effects on adherens junctions were assessed through the Western blotting of epithelial cadherin (E-cadherin) protein levels. Importantly, a drop in pH caused a rapid decrease in AT1 barrier resistance and increased the formation of a ~35 kDa E-cadherin C-terminal fragment, with both effects significantly reduced in TRPV4-/- AT1 cells. Similarly, the pharmacological activation of TRPV4 in AT1 cells triggered an immediate transient loss of barrier resistance and the formation of the same E-cadherin fragment, which was again diminished by TRPV4 deficiency. Moreover, TRPV4-mediated E-cadherin cleavage was significantly reduced by GI254023X, an antagonist of a disintegrin and metalloprotease 10 (ADAM10). Our results confirm the role of TRPV4 in regulating alveolar epithelial barrier permeability and provide insight into a novel signaling pathway by which TRPV4-induced Ca2+ influx stimulates metalloprotease-driven ectodomain shedding.
Collapse
Affiliation(s)
| | | | - Alexander Dietrich
- Walther Straub Institute for Pharmacology and Toxicology, Member of the German Center for Lung Research (DZL), Medical Faculty, LMU-Munich, Nussbaumstrasse 26, 80336 Munich, Germany; (L.S.); (T.G.)
| |
Collapse
|
|
5
|
Amoakon JP, Lee J, Liyanage P, Arora K, Karlstaedt A, Mylavarapu G, Amin R, Naren AP. Defective CFTR modulates mechanosensitive channels TRPV4 and PIEZO1 and drives endothelial barrier failure. iScience 2024; 27:110703. [PMID: 39252977 PMCID: PMC11382128 DOI: 10.1016/j.isci.2024.110703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 06/25/2024] [Accepted: 08/06/2024] [Indexed: 09/11/2024] Open
Abstract
Cystic fibrosis (CF) is a genetic disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Despite reports of CFTR expression on endothelial cells, pulmonary vascular perturbations, and perfusion deficits in CF patients, the mechanism of pulmonary vascular disease in CF remains unclear. Here, our pilot study of 40 CF patients reveals a loss of small pulmonary blood vessels in patients with severe lung disease. Using a vessel-on-a-chip model, we establish a shear-stress-dependent mechanism of endothelial barrier failure in CF involving TRPV4, a mechanosensitive channel. Furthermore, we demonstrate that CFTR deficiency downregulates the function of PIEZO1, another mechanosensitive channel involved in angiogenesis and wound repair, and exacerbates loss of small pulmonary blood vessel. We also show that CFTR directly interacts with PIEZO1 and enhances its function. Our study identifies key cellular targets to mitigate loss of small pulmonary blood vessels in CF.
Collapse
Affiliation(s)
- Jean-Pierre Amoakon
- Department of Systems Biology and Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Pulmonary Medicine and Critical Care, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jesun Lee
- Division of Pulmonary Medicine and Critical Care, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Pramodha Liyanage
- Division of Pulmonary Medicine and Critical Care, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Kavisha Arora
- Division of Pulmonary Medicine and Critical Care, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Anja Karlstaedt
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Goutham Mylavarapu
- Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Raouf Amin
- Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Anjaparavanda P Naren
- Department of Systems Biology and Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Pulmonary Medicine and Critical Care, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| |
Collapse
|
|
6
|
Zong P, Li CX, Feng J, Cicchetti M, Yue L. TRP Channels in Stroke. Neurosci Bull 2024; 40:1141-1159. [PMID: 37995056 PMCID: PMC11306852 DOI: 10.1007/s12264-023-01151-5] [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: 07/10/2023] [Accepted: 09/11/2023] [Indexed: 11/24/2023] Open
Abstract
Ischemic stroke is a devastating disease that affects millions of patients worldwide. Unfortunately, there are no effective medications for mitigating brain injury after ischemic stroke. TRP channels are evolutionally ancient biosensors that detect external stimuli as well as tissue or cellular injury. To date, many members of the TRP superfamily have been reported to contribute to ischemic brain injury, including the TRPC subfamily (1, 3, 4, 5, 6, 7), TRPV subfamily (1, 2, 3, 4) and TRPM subfamily (2, 4, 7). These TRP channels share structural similarities but have distinct channel functions and properties. Their activation during ischemic stroke can be beneficial, detrimental, or even both. In this review, we focus on discussing the interesting features of stroke-related TRP channels and summarizing the underlying cellular and molecular mechanisms responsible for their involvement in ischemic brain injury.
Collapse
Affiliation(s)
- Pengyu Zong
- Department of Cell Biology, Calhoun Cardiology Center, School of Medicine (UConn Health), University of Connecticut, Farmington, CT, 06030, USA.
- Institute for the Brain and Cognitive Sciences, University of Connecticut, 337 Mansfield Road, Unit 1272, Storrs, CT, 06269, USA.
| | - Cindy X Li
- Department of Cell Biology, Calhoun Cardiology Center, School of Medicine (UConn Health), University of Connecticut, Farmington, CT, 06030, USA
| | - Jianlin Feng
- Department of Cell Biology, Calhoun Cardiology Center, School of Medicine (UConn Health), University of Connecticut, Farmington, CT, 06030, USA
| | - Mara Cicchetti
- Department of Cell Biology, Calhoun Cardiology Center, School of Medicine (UConn Health), University of Connecticut, Farmington, CT, 06030, USA
- Department of Neuroscience, University of Pittsburgh, 4200 Fifth Ave, Pittsburgh, PA, 15260, USA
| | - Lixia Yue
- Department of Cell Biology, Calhoun Cardiology Center, School of Medicine (UConn Health), University of Connecticut, Farmington, CT, 06030, USA.
| |
Collapse
|
|
7
|
Bihari S, Costell MH, Bouchier T, Behm DJ, Burgert M, Ye G, Bersten AD, Puukila S, Cavallaro E, Sprecher DL, Dixon DL. Evaluation of GSK2789917-induced TRPV4 inhibition in animal models of fluid induced lung injury. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:3461-3475. [PMID: 37966569 DOI: 10.1007/s00210-023-02821-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 10/26/2023] [Indexed: 11/16/2023]
Abstract
Administration of bolus intravenous fluids, common in pre-hospital and hospitalised patients, is associated with increased lung vascular permeability and mortality outside underlying disease states. In our laboratory, the induction of lung injury and oedema through rapid administration of intravenous fluid in rats was reduced by a non-specific antagonist of transient receptor potential vanilloid 4 (TRPV4) channels. The aims of this study were to determine the effect of selective TRPV4 inhibition on fluid-induced lung injury (FILI) and compare the potency of FILI inhibition to that of an established model of TRPV4 agonist-induced lung oedema. In a series of experiments, rats received specific TRPV4 inhibitor (GSK2789917) at high (15 μg/kg), medium (5 μg/kg) or low (2 μg/kg) dose or vehicle prior to induction of lung injury by intravenous infusion of TRPV4 agonist (GSK1016790) or saline. GSK1016790 significantly increased lung wet weight/body weight ratio by 96% and lung wet-to-dry weight ratio by 43% in vehicle pre-treated rats, which was inhibited by GSK2789917 in a dose-dependent manner (IC50 = 3 ng/mL). Similarly, in a single-dose study, bolus saline infusion significantly increased lung wet weight/body weight by 17% and lung wet-to-dry weight ratio by 15%, which was attenuated by high dose GSK2789917. However, in a final GSK2789917 dose-response study, inhibition did not reach significance and an inhibitory potency was not determined due to the lack of a clear dose-response. In the FILI model, TRPV4 may have a role in lung injury induced by rapid-fluid infusion, indicated by inconsistent amelioration with high dose TRPV4 antagonist.
Collapse
Affiliation(s)
- Shailesh Bihari
- College of Medicine and Public Health, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia
- Intensive and Critical Care Unit, Flinders Medical Centre, Flinders Drive, Bedford Park, SA, 5042, Australia
| | - Melissa H Costell
- GlaxoSmithKline (GSK), 1250 South Collegeville Road, Collegeville, PA, 19426-0989, USA
| | - Tara Bouchier
- College of Medicine and Public Health, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia
| | - David J Behm
- GlaxoSmithKline (GSK), 1250 South Collegeville Road, Collegeville, PA, 19426-0989, USA
| | - Mark Burgert
- GlaxoSmithKline (GSK), 1250 South Collegeville Road, Collegeville, PA, 19426-0989, USA
| | - Guosen Ye
- GlaxoSmithKline (GSK), 1250 South Collegeville Road, Collegeville, PA, 19426-0989, USA
| | - Andrew D Bersten
- College of Medicine and Public Health, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia
- Intensive and Critical Care Unit, Flinders Medical Centre, Flinders Drive, Bedford Park, SA, 5042, Australia
| | - Stephanie Puukila
- College of Medicine and Public Health, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia
| | - Elena Cavallaro
- College of Medicine and Public Health, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia
| | - Dennis L Sprecher
- GlaxoSmithKline (GSK), 1250 South Collegeville Road, Collegeville, PA, 19426-0989, USA
| | - Dani-Louise Dixon
- College of Medicine and Public Health, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.
- Intensive and Critical Care Unit, Flinders Medical Centre, Flinders Drive, Bedford Park, SA, 5042, Australia.
| |
Collapse
|
|
8
|
Katari V, Dalal K, Adapala RK, Guarino BD, Kondapalli N, Paruchuri S, Thodeti CK. A TRP to Pathological Angiogenesis and Vascular Normalization. Compr Physiol 2024; 14:5389-5406. [PMID: 39109978 PMCID: PMC11998386 DOI: 10.1002/cphy.c230014] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
Uncontrolled angiogenesis underlies various pathological conditions such as cancer, age-related macular degeneration (AMD), and proliferative diabetic retinopathy (PDR). Hence, targeting pathological angiogenesis has become a promising strategy for the treatment of cancer and neovascular ocular diseases. However, current pharmacological treatments that target VEGF signaling have met with limited success either due to acquiring resistance against anti-VEGF therapies with serious side effects including nephrotoxicity and cardiovascular-related adverse effects in cancer patients or retinal vasculitis and intraocular inflammation after intravitreal injection in patients with AMD or PDR. Therefore, there is an urgent need to develop novel strategies which can control multiple aspects of the pathological microenvironment and regulate the process of abnormal angiogenesis. To this end, vascular normalization has been proposed as an alternative for antiangiogenesis approach; however, these strategies still focus on targeting VEGF or FGF or PDGF which has shown adverse effects. In addition to these growth factors, calcium has been recently implicated as an important modulator of tumor angiogenesis. This article provides an overview on the role of major calcium channels in endothelium, TRP channels, with a special focus on TRPV4 and its downstream signaling pathways in the regulation of pathological angiogenesis and vascular normalization. We also highlight recent findings on the modulation of TRPV4 activity and endothelial phenotypic transformation by tumor microenvironment through Rho/YAP/VEGFR2 mechanotranscriptional pathways. Finally, we provide perspective on endothelial TRPV4 as a novel VEGF alternative therapeutic target for vascular normalization and improved therapy. © 2024 American Physiological Society. Compr Physiol 14:5389-5406, 2024.
Collapse
Affiliation(s)
- Venkatesh Katari
- Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Kesha Dalal
- Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Ravi K. Adapala
- Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Brianna D. Guarino
- Vascular Research Lab, Providence Veterans Affairs Medical Center, Providence, Rhode Island, USA
- Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - Narendrababu Kondapalli
- Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Sailaja Paruchuri
- Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Charles K. Thodeti
- Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| |
Collapse
|
|
9
|
Moccia F, Brunetti V, Soda T, Berra-Romani R, Scarpellino G. Cracking the Endothelial Calcium (Ca 2+) Code: A Matter of Timing and Spacing. Int J Mol Sci 2023; 24:16765. [PMID: 38069089 PMCID: PMC10706333 DOI: 10.3390/ijms242316765] [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: 11/06/2023] [Revised: 11/16/2023] [Accepted: 11/24/2023] [Indexed: 12/18/2023] Open
Abstract
A monolayer of endothelial cells lines the innermost surface of all blood vessels, thereby coming into close contact with every region of the body and perceiving signals deriving from both the bloodstream and parenchymal tissues. An increase in intracellular Ca2+ concentration ([Ca2+]i) is the main mechanism whereby vascular endothelial cells integrate the information conveyed by local and circulating cues. Herein, we describe the dynamics and spatial distribution of endothelial Ca2+ signals to understand how an array of spatially restricted (at both the subcellular and cellular levels) Ca2+ signals is exploited by the vascular intima to fulfill this complex task. We then illustrate how local endothelial Ca2+ signals affect the most appropriate vascular function and are integrated to transmit this information to more distant sites to maintain cardiovascular homeostasis. Vasorelaxation and sprouting angiogenesis were selected as an example of functions that are finely tuned by the variable spatio-temporal profile endothelial Ca2+ signals. We further highlighted how distinct Ca2+ signatures regulate the different phases of vasculogenesis, i.e., proliferation and migration, in circulating endothelial precursors.
Collapse
Affiliation(s)
- Francesco Moccia
- Laboratory of General Physiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, 27100 Pavia, Italy; (V.B.); (G.S.)
| | - Valentina Brunetti
- Laboratory of General Physiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, 27100 Pavia, Italy; (V.B.); (G.S.)
| | - Teresa Soda
- Department of Health Sciences, University of Magna Graecia, 88100 Catanzaro, Italy;
| | - Roberto Berra-Romani
- Department of Biomedicine, School of Medicine, Benemérita Universidad Autónoma de Puebla, Puebla 72410, Mexico;
| | - Giorgia Scarpellino
- Laboratory of General Physiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, 27100 Pavia, Italy; (V.B.); (G.S.)
| |
Collapse
|
|
10
|
Ponce A, Larre I, Jimenez L, Roldán ML, Shoshani L, Cereijido M. Ouabain's Influence on TRPV4 Channels of Epithelial Cells: An Exploration of TRPV4 Activity, Expression, and Signaling Pathways. Int J Mol Sci 2023; 24:16687. [PMID: 38069012 PMCID: PMC10705919 DOI: 10.3390/ijms242316687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 11/16/2023] [Accepted: 11/21/2023] [Indexed: 12/18/2023] Open
Abstract
Ouabain, a substance originally obtained from plants, is now classified as a hormone because it is produced endogenously in certain animals, including humans. However, its precise effects on the body remain largely unknown. Previous studies have shown that ouabain can influence the phenotype of epithelial cells by affecting the expression of cell-cell molecular components and voltage-gated potassium channels. In this study, we conducted whole-cell clamp assays to determine whether ouabain affects the activity and/or expression of TRPV4 channels. Our findings indicate that ouabain has a statistically significant effect on the density of TRPV4 currents (dITRPV4), with an EC50 of 1.89 nM. Regarding treatment duration, dITRPV4 reaches its peak at around 1 h, followed by a subsequent decline and then a resurgence after 6 h, suggesting a short-term modulatory effect related to on TRPV4 channel activity and a long-term effect related to the promotion of synthesis of new TRPV4 channel units. The enhancement of dITRPV4 induced by ouabain was significantly lower in cells seeded at low density than in cells in a confluent monolayer, indicating that the action of ouabain depends on intercellular contacts. Furthermore, the fact that U73122 and neomycin suppress the effect caused by ouabain in the short term suggests that the short-term induced enhancement of dITRPV4 is due to the depletion of PIP2 stores. In contrast, the fact that the long-term effect is inhibited by PP2, wortmannin, PD, FR18, and IKK16 suggests that cSrc, PI3K, Erk1/2, and NF-kB are among the components included in the signaling pathways.
Collapse
Affiliation(s)
- Arturo Ponce
- Department of Physiology, Biophysics and Neurosciences, CINVESTAV-IPN, Mexico City 07360, Mexico; (L.J.); (M.L.R.); (L.S.); (M.C.)
| | - Isabel Larre
- Department of Physiology, Faculty of Medicine, Universidad Nacional Autónoma de Mexico (UNAM), Mexico City 04510, Mexico;
- Department of Clinical and Translational Science, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
| | - Lidia Jimenez
- Department of Physiology, Biophysics and Neurosciences, CINVESTAV-IPN, Mexico City 07360, Mexico; (L.J.); (M.L.R.); (L.S.); (M.C.)
| | - Maria Luisa Roldán
- Department of Physiology, Biophysics and Neurosciences, CINVESTAV-IPN, Mexico City 07360, Mexico; (L.J.); (M.L.R.); (L.S.); (M.C.)
| | - Liora Shoshani
- Department of Physiology, Biophysics and Neurosciences, CINVESTAV-IPN, Mexico City 07360, Mexico; (L.J.); (M.L.R.); (L.S.); (M.C.)
| | - Marcelino Cereijido
- Department of Physiology, Biophysics and Neurosciences, CINVESTAV-IPN, Mexico City 07360, Mexico; (L.J.); (M.L.R.); (L.S.); (M.C.)
| |
Collapse
|
|
11
|
Shemarova I. The Dysfunction of Ca 2+ Channels in Hereditary and Chronic Human Heart Diseases and Experimental Animal Models. Int J Mol Sci 2023; 24:15682. [PMID: 37958665 PMCID: PMC10650855 DOI: 10.3390/ijms242115682] [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: 09/11/2023] [Revised: 10/20/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Chronic heart diseases, such as coronary heart disease, heart failure, secondary arterial hypertension, and dilated and hypertrophic cardiomyopathies, are widespread and have a fairly high incidence of mortality and disability. Most of these diseases are characterized by cardiac arrhythmias, conduction, and contractility disorders. Additionally, interruption of the electrical activity of the heart, the appearance of extensive ectopic foci, and heart failure are all symptoms of a number of severe hereditary diseases. The molecular mechanisms leading to the development of heart diseases are associated with impaired permeability and excitability of cell membranes and are mainly caused by the dysfunction of cardiac Ca2+ channels. Over the past 50 years, more than 100 varieties of ion channels have been found in the cardiovascular cells. The relationship between the activity of these channels and cardiac pathology, as well as the general cellular biological function, has been intensively studied on several cell types and experimental animal models in vivo and in situ. In this review, I discuss the origin of genetic Ca2+ channelopathies of L- and T-type voltage-gated calcium channels in humans and the role of the non-genetic dysfunctions of Ca2+ channels of various types: L-, R-, and T-type voltage-gated calcium channels, RyR2, including Ca2+ permeable nonselective cation hyperpolarization-activated cyclic nucleotide-gated (HCN), and transient receptor potential (TRP) channels, in the development of cardiac pathology in humans, as well as various aspects of promising experimental studies of the dysfunctions of these channels performed on animal models or in vitro.
Collapse
Affiliation(s)
- Irina Shemarova
- I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223 Saint-Petersburg, Russia
| |
Collapse
|
|
12
|
Wen X, Peng Y, Peng Y, Zhu Y, Yu F, Geng L, Zhou T, Wang X, Feng L, Meng Q. Aortic smooth muscle TRPV4 channels regulate vasoconstriction in high salt-induced hypertension. Hypertens Res 2023; 46:2356-2367. [PMID: 37532951 DOI: 10.1038/s41440-023-01363-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 06/21/2023] [Accepted: 06/23/2023] [Indexed: 08/04/2023]
Abstract
Recent studies have focused on the contribution of vascular endothelial transient receptor potential vanilloid 4 (TRPV4) channels to hypertension. However, in hypertension, TRPV4 channels in vascular smooth muscle remain unexplored. In the present study, we performed wire myograph experiments in isolated aortas from endothelial cell specific TRPV4 channel knockout (TRPV4EC-/-) mice to demonstrate that GSK1016790A (a specific TRPV4 channel agonist) triggered aortic smooth muscle-dependent contractions from mice on a normal-salt diet, and the contractions were enhanced in high-salt diet (HSD) mice. Intracellular Ca2+ concentration ([Ca2+]i) and Ca2+ imaging assays showed that TRPV4-induced [Ca2+]i was significantly higher in aortic smooth muscle cells (ASMCs) from HSD-induced hypertensive mice, and application of an inositol trisphosphate receptor (IP3R) inhibitor markedly attenuated TRPV4-induced [Ca2+]i. IP3R2 expression was enhanced in ASMCs from HSD-induced hypertensive mice and the contractile response induced by TRPV4 was inhibited by the IP3R inhibitor. Whole-transcriptome analysis by RNA-seq and western blot assays revealed the involvement of interferon regulatory factor 7 (IRF7) in TRPV4-IRF7-IP3R2 signaling in HSD-induced hypertension. These results suggested that TRPV4 channels regulate smooth muscle-dependent contractions in high salt-induced hypertension, and this contraction involves increased [Ca2+]i, IP3R2, and IRF7 activity. Our study revealed a considerable effect of TRPV4 channels in smooth muscle-dependent contraction in mice during high-salt induced hypertension.
Collapse
Affiliation(s)
- Xin Wen
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China
| | - Yidi Peng
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, 214000, China
| | - Yuefeng Peng
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China
| | - Yuzhong Zhu
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China
| | - Fan Yu
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China
| | - Li Geng
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China
| | - Tingting Zhou
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China
| | - Xianfeng Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China
| | - Lei Feng
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China
| | - Qingyou Meng
- Department of Vascular Surgery, General Surgery Clinical Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| |
Collapse
|
|
13
|
Li X, Hu J, Yin P, Liu L, Chen Y. Mechanotransduction in the urothelium: ATP signalling and mechanoreceptors. Heliyon 2023; 9:e19427. [PMID: 37674847 PMCID: PMC10477517 DOI: 10.1016/j.heliyon.2023.e19427] [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: 04/23/2023] [Revised: 08/10/2023] [Accepted: 08/22/2023] [Indexed: 09/08/2023] Open
Abstract
The urothelium, which covers the inner surface of the bladder, is continuously exposed to a complex physical environment where it is stimulated by, and responds to, a wide range of mechanical cues. Mechanically activated ion channels endow the urothelium with functioning in the conversion of mechanical stimuli into biochemical events that influence the surface of the urothelium itself as well as suburothelial tissues, including afferent nerve fibres, interstitial cells of Cajal and detrusor smooth muscle cells, to ensure normal urinary function during the cycle of filling and voiding. However, under prolonged and abnormal loading conditions, the urothelial sensory system can become maladaptive, leading to the development of bladder dysfunction. In this review, we summarize developments in the understanding of urothelial mechanotransduction from two perspectives: first, with regard to the functions of urothelial mechanotransduction, particularly stretch-mediated ATP signalling and the regulation of urothelial surface area; and secondly, with regard to the mechanoreceptors present in the urothelium, primarily transient receptor potential channels and mechanosensitive Piezo channels, and the potential pathophysiological role of these channels in the bladder. A more thorough understanding of urothelial mechanotransduction function may inspire the development of new therapeutic strategies for lower urinary tract diseases.
Collapse
Affiliation(s)
| | | | - Ping Yin
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Lumin Liu
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Yuelai Chen
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| |
Collapse
|
|
14
|
Liu G, Liu J, Kong X, Xiong WJ, Jiang R. Effect of hypoandrogenism on expression of transient receptor potential vanilloid channels in rat penile corpus cavernosum and erectile function. J Sex Med 2023; 20:1153-1160. [PMID: 37490314 DOI: 10.1093/jsxmed/qdad093] [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: 03/07/2023] [Revised: 06/16/2023] [Accepted: 06/20/2023] [Indexed: 07/26/2023]
Abstract
BACKGROUND Hypoandrogenism is a cause of erectile dysfunction (ED). Vascular smooth muscle cell contraction and relaxation are regulated by TRPV1-4 channels. However, the influence of hypoandrogenism on TRPV1-4 and its relationship with erectile function remain unclear. AIM To reveal whether hypoandrogenism affects erectile function by influencing TRPV1-4 expression in the corpus cavernosum of rats. METHODS Male Sprague-Dawley rats (N = 36) aged 8 weeks were assigned to 6 groups at random (n = 6): sham operation, castrated, castrated + testosterone replacement, sham operation + transfection, castrated + transfection, and castrated + empty transfection. Four weeks after castration, 20 μL of lentiviral vector (1 × 108 TU/mL) carrying the TRPV4 gene was injected into the penile cavernous tissue of the transfection groups. One week after transfection, the maximum intracavernous pressure (ICPmax)/mean arterial pressure (MAP) and the content of TRPV1-4, phosphorylated eNOS (p-eNOS)/eNOS, and nitric oxide (NO) in penile cavernous tissue of each group were measured. OUTCOMES Under low androgen conditions, TRPV4 expression in endothelial cells in the rat penile cavernosum was sharply reduced, resulting in a decrease in p-eNOS/eNOS and NO content, which could inhibit erectile function. RESULTS In rat penile cavernous tissue, TRPV1-4 was expressed in the cell membranes of endothelial cells and smooth muscle cells. The ICPmax/MAP and the content of TRPV4, p-eNOS/eNOS, and NO end product nitrite level in rat penile cavernous tissue was markedly reduced in the castrated group as compared with the sham group (P < .05). The ICPmax/MAP and the content of TRPV4, p-eNOS/eNOS, and NO end product nitrite level in rat penile cavernous tissue were markedly improved in the castrated + transfection group vs the castrated group (P < .01). CLINICAL IMPLICATIONS Upregulation of TRPV4 expression in penile cavernosum tissue might be a viable therapeutic for ED caused by hypoandrogenism. STRENGTHS AND LIMITATIONS The specific mechanism of TRPV4 in ED needs to be further verified by androgen receptor or TRPV4 gene knockout experiments. CONCLUSION Hypoandrogenism may cause ED by reducing the expression of TRPV4 in rat penile cavernous tissue. Upregulation of TRPV4 expression in penile cavernous tissue can increase the ratio of p-eNOS/eNOS and NO levels and ameliorate the erectile function of castrated rats.
Collapse
Affiliation(s)
- Gang Liu
- Department of Urology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Jing Liu
- Department of Urology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Xiangjun Kong
- Department of Urology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Wen-Ju Xiong
- Department of Urology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Rui Jiang
- Department of Urology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| |
Collapse
|
|
15
|
Chaigne S, Barbeau S, Ducret T, Guinamard R, Benoist D. Pathophysiological Roles of the TRPV4 Channel in the Heart. Cells 2023; 12:1654. [PMID: 37371124 DOI: 10.3390/cells12121654] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/10/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
The transient receptor potential vanilloid 4 (TRPV4) channel is a non-selective cation channel that is mostly permeable to calcium (Ca2+), which participates in intracellular Ca2+ handling in cardiac cells. It is widely expressed through the body and is activated by a large spectrum of physicochemical stimuli, conferring it a role in a variety of sensorial and physiological functions. Within the cardiovascular system, TRPV4 expression is reported in cardiomyocytes, endothelial cells (ECs) and smooth muscle cells (SMCs), where it modulates mitochondrial activity, Ca2+ homeostasis, cardiomyocytes electrical activity and contractility, cardiac embryonic development and fibroblast proliferation, as well as vascular permeability, dilatation and constriction. On the other hand, TRPV4 channels participate in several cardiac pathological processes such as the development of cardiac fibrosis, hypertrophy, ischemia-reperfusion injuries, heart failure, myocardial infarction and arrhythmia. In this manuscript, we provide an overview of TRPV4 channel implications in cardiac physiology and discuss the potential of the TRPV4 channel as a therapeutic target against cardiovascular diseases.
Collapse
Affiliation(s)
- Sébastien Chaigne
- IHU LIRYC Electrophysiology and Heart Modeling Institute, Fondation Bordeaux Université, 33600 Bordeaux, France
- Centre de Recherche Cardio-Thoracique de Bordeaux, INSERM U1045, University of Bordeaux, 33600 Pessac, France
- Electrophysiology and Ablation Unit, Bordeaux University Hospital, 33604 Pessac, France
| | - Solène Barbeau
- Centre de Recherche Cardio-Thoracique de Bordeaux, INSERM U1045, University of Bordeaux, 33600 Pessac, France
| | - Thomas Ducret
- Centre de Recherche Cardio-Thoracique de Bordeaux, INSERM U1045, University of Bordeaux, 33600 Pessac, France
| | - Romain Guinamard
- UR4650, Physiopathologie et Stratégies d'Imagerie du Remodelage Cardiovasculaire, GIP Cyceron, Université de Caen Normandie, 14032 Caen, France
| | - David Benoist
- IHU LIRYC Electrophysiology and Heart Modeling Institute, Fondation Bordeaux Université, 33600 Bordeaux, France
- Centre de Recherche Cardio-Thoracique de Bordeaux, INSERM U1045, University of Bordeaux, 33600 Pessac, France
| |
Collapse
|
|
16
|
Petrova RS, Nair N, Bavana N, Chen Y, Schey KL, Donaldson PJ. Modulation of Membrane Trafficking of AQP5 in the Lens in Response to Changes in Zonular Tension Is Mediated by the Mechanosensitive Channel TRPV1. Int J Mol Sci 2023; 24:9080. [PMID: 37240426 PMCID: PMC10219244 DOI: 10.3390/ijms24109080] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/16/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023] Open
Abstract
In mice, the contraction of the ciliary muscle via the administration of pilocarpine reduces the zonular tension applied to the lens and activates the TRPV1-mediated arm of a dual feedback system that regulates the lens' hydrostatic pressure gradient. In the rat lens, this pilocarpine-induced reduction in zonular tension also causes the water channel AQP5 to be removed from the membranes of fiber cells located in the anterior influx and equatorial efflux zones. Here, we determined whether this pilocarpine-induced membrane trafficking of AQP5 is also regulated by the activation of TRPV1. Using microelectrode-based methods to measure surface pressure, we found that pilocarpine also increased pressure in the rat lenses via the activation of TRPV1, while pilocarpine-induced removal of AQP5 from the membrane observed using immunolabelling was abolished by pre-incubation of the lenses with a TRPV1 inhibitor. In contrast, mimicking the actions of pilocarpine by blocking TRPV4 and then activating TRPV1 resulted in sustained increase in pressure and the removal of AQP5 from the anterior influx and equatorial efflux zones. These results show that the removal of AQP5 in response to a decrease in zonular tension is mediated by TRPV1 and suggest that regional changes to PH2O contribute to lens hydrostatic pressure gradient regulation.
Collapse
Affiliation(s)
- Rosica S. Petrova
- Department of Physiology, School of Medical Sciences, New Zealand National Eye Center, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand
| | - Nikhil Nair
- Department of Physiology, School of Medical Sciences, New Zealand National Eye Center, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand
| | - Nandini Bavana
- Department of Physiology, School of Medical Sciences, New Zealand National Eye Center, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand
| | - Yadi Chen
- Department of Physiology, School of Medical Sciences, New Zealand National Eye Center, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand
| | - Kevin L. Schey
- Department of Biochemistry, Mass Spectrometry Research Center, Vanderbilt University, Nashville, TN 37232, USA
| | - Paul J. Donaldson
- Department of Physiology, School of Medical Sciences, New Zealand National Eye Center, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand
| |
Collapse
|
|
17
|
Kumar M, Zaman MK, Das S, Goyary D, Pathak MP, Chattopadhyay P. Transient Receptor Potential Vanilloid (TRPV4) channel inhibition: A novel promising approach for the treatment of lung diseases. Biomed Pharmacother 2023; 163:114861. [PMID: 37178575 DOI: 10.1016/j.biopha.2023.114861] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/03/2023] [Accepted: 05/06/2023] [Indexed: 05/15/2023] Open
Abstract
Research on transient receptor potential vanilloid-4 (TRPV4) can provide a promising potential therapeutic target in the development of novel medicines for lung disorders. TRPV4 expresses in lung tissue and plays an important role in the maintenance of respiratory homeostatic function. TRPV4 is upregulated in life-threatening respiratory diseases like pulmonary hypertension, asthma, cystic fibrosis, and chronic obstructive pulmonary diseases. TRPV4 is linked to several proteins that have physiological functions and are sensitive to a wide variety of stimuli, such as mechanical stimulation, changes in temperature, and hypotonicity, and responds to a variety of proteins and lipid mediators, including anandamide (AA), the arachidonic acid metabolite, 5,6-epoxyeicosatrienoic acid (5,6-EET), a plant dimeric diterpenoid called bisandrographolide A (BAA), and the phorbol ester 4-alpha-phorbol-12,13-didecanoate (4α-PDD). This study focused on relevant research evidence of TRPV4 in lung disorders and its agonist and antagonist effects. TRPV4 can be a possible target of discovered molecules that exerts high therapeutic potential in the treatment of respiratory diseases by inhibiting TRPV4.
Collapse
Affiliation(s)
- Mohit Kumar
- Division of Pharmaceutical Technology, Defence Research Laboratory, Tezpur, Assam 784001, India; Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam 786004, India
| | - Md Kamaruz Zaman
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam 786004, India
| | - Sanghita Das
- Division of Pharmaceutical Technology, Defence Research Laboratory, Tezpur, Assam 784001, India; Pharmaceutical & Fine Chemical Division, Department of Chemical Technology, University of Calcutta, Kolkata, West Bengal 700073, India
| | - Danswrang Goyary
- Division of Pharmaceutical Technology, Defence Research Laboratory, Tezpur, Assam 784001, India
| | - Manash Pratim Pathak
- Faculty of Pharmaceutical Science, Assam down town University, Guwahati, Assam 781026, India.
| | - Pronobesh Chattopadhyay
- Division of Pharmaceutical Technology, Defence Research Laboratory, Tezpur, Assam 784001, India.
| |
Collapse
|
|
18
|
Dryn DO, Melnyk MI, Melanaphy D, Kizub IV, Johnson CD, Zholos AV. Bidirectional TRP/L Type Ca 2+ Channel/RyR/BK Ca Molecular and Functional Signaloplex in Vascular Smooth Muscles. Biomolecules 2023; 13:biom13050759. [PMID: 37238629 DOI: 10.3390/biom13050759] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/24/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023] Open
Abstract
TRP channels are expressed both in vascular myocytes and endothelial cells, but knowledge of their operational mechanisms in vascular tissue is particularly limited. Here, we show for the first time the biphasic contractile reaction with relaxation followed by a contraction in response to TRPV4 agonist, GSK1016790A, in a rat pulmonary artery preconstricted with phenylephrine. Similar responses were observed both with and without endothelium, and these were abolished by the TRPV4 selective blocker, HC067047, confirming the specific role of TRPV4 in vascular myocytes. Using selective blockers of BKCa and L-type voltage-gated Ca2+ channels (CaL), we found that the relaxation phase was inducted by BKCa activation generating STOCs, while subsequent slowly developing TRPV4-mediated depolarisation activated CaL, producing the second contraction phase. These results are compared to TRPM8 activation using menthol in rat tail artery. Activation of both types of TRP channels produces highly similar changes in membrane potential, namely slow depolarisation with concurrent brief hyperpolarisations due to STOCs. We thus propose a general concept of bidirectional TRP-CaL-RyR-BKCa molecular and functional signaloplex in vascular smooth muscles. Accordingly, both TRPV4 and TRPM8 channels enhance local Ca2+ signals producing STOCs via TRP-RyR-BKCa coupling while simultaneously globally engaging BKCa and CaL channels by altering membrane potential.
Collapse
Affiliation(s)
- Dariia O Dryn
- O.O. Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, 01024 Kyiv, Ukraine
| | - Mariia I Melnyk
- O.O. Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, 01024 Kyiv, Ukraine
- ESC "Institute of Biology and Medicine", Taras Shevchenko National University of Kyiv, 01601 Kyiv, Ukraine
| | - Donal Melanaphy
- Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast BT9 7BL, UK
| | - Igor V Kizub
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Christopher D Johnson
- Centre for Biomedical Sciences Education, Queen's University Belfast, Whitla Medical Building, Belfast BT9 7BL, UK
| | - Alexander V Zholos
- ESC "Institute of Biology and Medicine", Taras Shevchenko National University of Kyiv, 01601 Kyiv, Ukraine
| |
Collapse
|
|
19
|
Tureckova J, Hermanova Z, Marchetti V, Anderova M. Astrocytic TRPV4 Channels and Their Role in Brain Ischemia. Int J Mol Sci 2023; 24:ijms24087101. [PMID: 37108263 PMCID: PMC10138480 DOI: 10.3390/ijms24087101] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/06/2023] [Accepted: 04/08/2023] [Indexed: 04/29/2023] Open
Abstract
Transient receptor potential cation channels subfamily V member 4 (TRPV4) are non-selective cation channels expressed in different cell types of the central nervous system. These channels can be activated by diverse physical and chemical stimuli, including heat and mechanical stress. In astrocytes, they are involved in the modulation of neuronal excitability, control of blood flow, and brain edema formation. All these processes are significantly impaired in cerebral ischemia due to insufficient blood supply to the tissue, resulting in energy depletion, ionic disbalance, and excitotoxicity. The polymodal cation channel TRPV4, which mediates Ca2+ influx into the cell because of activation by various stimuli, is one of the potential therapeutic targets in the treatment of cerebral ischemia. However, its expression and function vary significantly between brain cell types, and therefore, the effect of its modulation in healthy tissue and pathology needs to be carefully studied and evaluated. In this review, we provide a summary of available information on TRPV4 channels and their expression in healthy and injured neural cells, with a particular focus on their role in ischemic brain injury.
Collapse
Affiliation(s)
- Jana Tureckova
- Institute of Experimental Medicine, Czech Academy of Sciences, 1083 Videnska, 142 20 Prague, Czech Republic
| | - Zuzana Hermanova
- Institute of Experimental Medicine, Czech Academy of Sciences, 1083 Videnska, 142 20 Prague, Czech Republic
- Second Faculty of Medicine, Charles University, 84 V Uvalu, 150 06 Prague, Czech Republic
| | - Valeria Marchetti
- Institute of Experimental Medicine, Czech Academy of Sciences, 1083 Videnska, 142 20 Prague, Czech Republic
- Second Faculty of Medicine, Charles University, 84 V Uvalu, 150 06 Prague, Czech Republic
| | - Miroslava Anderova
- Institute of Experimental Medicine, Czech Academy of Sciences, 1083 Videnska, 142 20 Prague, Czech Republic
- Second Faculty of Medicine, Charles University, 84 V Uvalu, 150 06 Prague, Czech Republic
| |
Collapse
|
|
20
|
Blazer-Yost BL. Consideration of Kinase Inhibitors for the Treatment of Hydrocephalus. Int J Mol Sci 2023; 24:ijms24076673. [PMID: 37047646 PMCID: PMC10094860 DOI: 10.3390/ijms24076673] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/27/2023] [Accepted: 03/29/2023] [Indexed: 04/07/2023] Open
Abstract
Hydrocephalus is a devastating condition characterized by excess cerebrospinal fluid (CSF) in the brain. Currently, the only effective treatment is surgical intervention, usually involving shunt placement, a procedure prone to malfunction, blockage, and infection that requires additional, often repetitive, surgeries. There are no long-term pharmaceutical treatments for hydrocephalus. To initiate an intelligent drug design, it is necessary to understand the biochemical changes underlying the pathology of this chronic condition. One potential commonality in the various forms of hydrocephalus is an imbalance in fluid–electrolyte homeostasis. The choroid plexus, a complex tissue found in the brain ventricles, is one of the most secretory tissues in the body, producing approximately 500 mL of CSF per day in an adult human. In this manuscript, two key transport proteins of the choroid plexus epithelial cells, transient receptor potential vanilloid 4 and sodium, potassium, 2 chloride co-transporter 1, will be considered. Both appear to play key roles in CSF production, and their inhibition or genetic manipulation has been shown to affect CSF volume. As with most transporters, these proteins are regulated by kinases. Therefore, specific kinase inhibitors are also potential targets for the development of pharmaceuticals to treat hydrocephalus.
Collapse
Affiliation(s)
- Bonnie L. Blazer-Yost
- Biology Department, Indiana University—Purdue University, 723 West Michigan Street, Indianapolis, IN 46202, USA
| |
Collapse
|
|
21
|
Zeng ML, Kong S, Chen TX, Peng BW. Transient Receptor Potential Vanilloid 4: a Double-Edged Sword in the Central Nervous System. Mol Neurobiol 2023; 60:1232-1249. [PMID: 36434370 DOI: 10.1007/s12035-022-03141-6] [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: 08/09/2022] [Accepted: 11/17/2022] [Indexed: 11/26/2022]
Abstract
Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel that can be activated by diverse stimuli, such as heat, mechanical force, hypo-osmolarity, and arachidonic acid metabolites. TRPV4 is widely expressed in the central nervous system (CNS) and participates in many significant physiological processes. However, accumulative evidence has suggested that deficiency, abnormal expression or distribution, and overactivation of TRPV4 are involved in pathological processes of multiple neurological diseases. Here, we review the latest studies concerning the known features of this channel, including its expression, structure, and its physiological and pathological roles in the CNS, proposing an emerging therapeutic strategy for CNS diseases.
Collapse
Affiliation(s)
- Meng-Liu Zeng
- Department of Physiology, Hubei Provincial Key Laboratory of Developmentally Originated Disease, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Donghu Rd185#, Wuhan, 430071, Hubei, China.,Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Shuo Kong
- Department of Physiology, Hubei Provincial Key Laboratory of Developmentally Originated Disease, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Donghu Rd185#, Wuhan, 430071, Hubei, China
| | - Tao-Xiang Chen
- Department of Physiology, Hubei Provincial Key Laboratory of Developmentally Originated Disease, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Donghu Rd185#, Wuhan, 430071, Hubei, China
| | - Bi-Wen Peng
- Department of Physiology, Hubei Provincial Key Laboratory of Developmentally Originated Disease, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Donghu Rd185#, Wuhan, 430071, Hubei, China.
| |
Collapse
|
|
22
|
Zhang L, Xu Y, Ma Y, Xie T, Liu C, Liu Q. Research trends in transient receptor potential vanilloid in cardiovascular disease: Bibliometric analysis and visualization. Front Cardiovasc Med 2023; 10:1071198. [PMID: 36910533 PMCID: PMC9992894 DOI: 10.3389/fcvm.2023.1071198] [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: 10/15/2022] [Accepted: 02/02/2023] [Indexed: 02/24/2023] Open
Abstract
Background Transient receptor potential vanilloid (TRPV) is one of the transient receptor potential protein groups; cardiovascular system disease is a crucial cause of mortality among people globally. Objective This article is intended to accomplish a bibliometric analysis of the trends and public interest since TRPV was reported for the first time. Methods The article summarized the Web of Science (WOS) Core Collection on the relationship between TRPV and cardiovascular system disease each year from 2000 to 2021. Data extraction and visualization were completed by R package bibliometrix. Keyword citation burst and co-citation networks were generated and produced by CiteSpace. The map evaluating the distribution of country and region was painted in GunnMap 2 (lert.co.nz). The ranking was performed using the Standard Competition Ranking method. Co-authorship and co-occurrence were analyzed with VOSviewer. Results After removing duplicated data, books, conference proceedings, and articles of uncertain age, 493 were included, and 17 were excluded. The pattern of publication years showed that the number of publications increased rapidly from 2008 to 2021 with no peak in the number of publications until 2021. The geographical distribution pattern revealed a considerable gap in the number of publications between the United States, China, and other countries, with East Asian institutions leading the world in this area. The pattern of co-authorship showed that 77 institutions were divided into 19 clusters, each covering one country or region.These results suggest that intercontinental cooperation among institutions should be strengthened. The core authors section displayed the change in the most published authors. Keyword analysis listed six burst keywords. Co-citation analysis of references from 2011 to 2021 showed the number and centrality of citations to leading articles. Conclusion Our findings reveal trends and public interest in transient receptor potential vanilloid for cardiovascular disease. These findings suggest that the field has experienced significant growth since 2008, with the United States and China in dominant positions. Our findings also suggest that intercontinental cooperation should be strengthened, and that future research hotspots may focus on pharmacological mechanisms and in-depth exploration of drug clinical trials and new clinical disease application areas such as hypertension, diabetes, and cardiac arrhythmias, which could serve as a foundation for further research.
Collapse
Affiliation(s)
- Lingfeng Zhang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha, China.,Xiangya School of Medicine, Central South University, Changsha, China
| | - Yantao Xu
- Xiangya School of Medicine, Central South University, Changsha, China.,Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
| | - Yingxu Ma
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Tianjian Xie
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Chan Liu
- International Medical Department, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Qiming Liu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha, China.,Xiangya School of Medicine, Central South University, Changsha, China
| |
Collapse
|
|
23
|
Erfinanda L, Zou L, Gutbier B, Kneller L, Weidenfeld S, Michalick L, Lei D, Reppe K, Teixeira Alves LG, Schneider B, Zhang Q, Li C, Fatykhova D, Schneider P, Liedtke W, Sohara E, Mitchell TJ, Gruber AD, Hocke A, Hippenstiel S, Suttorp N, Olschewski A, Mall MA, Witzenrath M, Kuebler WM. Loss of endothelial CFTR drives barrier failure and edema formation in lung infection and can be targeted by CFTR potentiation. Sci Transl Med 2022; 14:eabg8577. [PMID: 36475904 DOI: 10.1126/scitranslmed.abg8577] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Pneumonia is the most common cause of the acute respiratory distress syndrome (ARDS). Here, we identified loss of endothelial cystic fibrosis transmembrane conductance regulator (CFTR) as an important pathomechanism leading to lung barrier failure in pneumonia-induced ARDS. CFTR was down-regulated after Streptococcus pneumoniae infection ex vivo or in vivo in human or murine lung tissue, respectively. Analysis of isolated perfused rat lungs revealed that CFTR inhibition increased endothelial permeability in parallel with intracellular chloride ion and calcium ion concentrations ([Cl-]i and [Ca2+]i). Inhibition of the chloride ion-sensitive with-no-lysine kinase 1 (WNK1) protein with tyrphostin 47 or WNK463 replicated the effect of CFTR inhibition on endothelial permeability and endothelial [Ca2+]i, whereas WNK1 activation by temozolomide attenuated it. Endothelial [Ca2+]i transients and permeability in response to inhibition of either CFTR or WNK1 were prevented by inhibition of the cation channel transient receptor potential vanilloid 4 (TRPV4). Mice deficient in Trpv4 (Trpv4-/-) developed less lung edema and protein leak than their wild-type littermates after infection with S. pneumoniae. The CFTR potentiator ivacaftor prevented lung CFTR loss, edema, and protein leak after S. pneumoniae infection in wild-type mice. In conclusion, lung infection caused loss of CFTR that promoted lung edema formation through intracellular chloride ion accumulation, inhibition of WNK1, and subsequent disinhibition of TRPV4, resulting in endothelial calcium ion influx and vascular barrier failure. Ivacaftor prevented CFTR loss in the lungs of mice with pneumonia and may, therefore, represent a possible therapeutic strategy in people suffering from ARDS due to severe pneumonia.
Collapse
Affiliation(s)
- Lasti Erfinanda
- Institute of Physiology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Lin Zou
- Institute of Physiology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.,German Heart Center, 13353 Berlin, Germany.,Department of Endocrinology, Shanghai Pudong New Area Gongli Hospital, 200135 Shanghai, China
| | - Birgitt Gutbier
- Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
| | - Laura Kneller
- Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
| | - Sarah Weidenfeld
- Institute of Physiology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Laura Michalick
- Institute of Physiology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Disi Lei
- Institute of Physiology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.,German Heart Center, 13353 Berlin, Germany
| | - Katrin Reppe
- Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
| | - Luiz Gustavo Teixeira Alves
- Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
| | - Bill Schneider
- Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
| | - Qi Zhang
- Institute of Physiology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Caihong Li
- Institute of Physiology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Diana Fatykhova
- Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
| | - Paul Schneider
- Department for General and Thoracic Surgery, DRK Clinics, 13359 Berlin, Germany
| | - Wolfgang Liedtke
- Departments of Neurology, Neurobiology, and Clinics for Pain and Palliative Care, Duke University Medical Center, Durham, NC 27710, USA
| | - Eisei Sohara
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Timothy J Mitchell
- Institute of Microbiology and Infection, University of Birmingham, Birmingham B15-2TT, UK
| | - Achim D Gruber
- Institute of Veterinary Pathology, Freie Universität Berlin, 14163 Berlin, Germany
| | - Andreas Hocke
- Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.,German Center for Lung Research (DZL), associated partner site, 10117 Berlin, Germany
| | - Stefan Hippenstiel
- Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.,German Center for Lung Research (DZL), associated partner site, 10117 Berlin, Germany
| | - Norbert Suttorp
- Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.,German Center for Lung Research (DZL), associated partner site, 10117 Berlin, Germany
| | - Andrea Olschewski
- Experimental Anaesthesiology, Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, 8010 Graz, Austria
| | - Marcus A Mall
- German Center for Lung Research (DZL), associated partner site, 10117 Berlin, Germany.,Department of Pediatric Pulmonology, Immunology and Intensive Care Medicine, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Martin Witzenrath
- Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.,German Center for Lung Research (DZL), associated partner site, 10117 Berlin, Germany
| | - Wolfgang M Kuebler
- Institute of Physiology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.,German Center for Lung Research (DZL), associated partner site, 10117 Berlin, Germany
| |
Collapse
|
|
24
|
Hayakawa S, Tanaka T, Ogawa R, Ito S, Ueno S, Koyama H, Tomotaka O, Sagawa H, Tanaka T, Iwakura H, Takahashi H, Matsuo Y, Mitsui A, Kimura M, Takahashi S, Takiguchi S. Potential Role of TRPV4 in Stretch-Induced Ghrelin Secretion and Obesity. Int J Endocrinol 2022; 2022:7241275. [PMID: 36397882 PMCID: PMC9666045 DOI: 10.1155/2022/7241275] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 10/18/2022] [Accepted: 10/25/2022] [Indexed: 11/09/2022] Open
Abstract
Obesity is an important health problem, which can be prevented through appetite control. Ghrelin is an appetite-stimulating hormone considered to promote obesity. Thus, we examined whether gastric stretching affects ghrelin secretion. We investigated the role of transient receptor potential vanilloid 4 (TRPV4) in gastric glands in the regulation of ghrelin secretion. TRPV4 immunostaining was performed in tissue samples from 57 patients who underwent gastrectomy. TRPV4 expression was compared between patients with (body mass index (BMI) ≥ 30) and without (BMI <30) obesity. For in vitro experiments, we used MGN3-1 cells, a ghrelin-producing cell line derived from mice. To investigate the bioactivity of TRPV4, MGN3-1 cells were treated with TRPV4 agonists and antagonists, and changes in intracellular Ca2+ concentration were confirmed. The concentration of ghrelin in the cell supernatant was measured using the ELISA with and without 120% stretch stimulation. TRPV4 expression was significantly higher in patients with obesity than in those without at all sites, except the fornix. Immunostaining confirmed the expression of TRPV4 in MGN3-1 cells. TRPV4 agonist administration increased intracellular Ca2+ concentration and ghrelin secretion in MGN3-1 cells, whereas the administration of the agonist combined with the antagonist decreased intracellular Ca2+ concentration and ghrelin secretion. Ghrelin secretion significantly increased in response to a 120% stretch in MGN3-1 cells. However, secretion was not increased by stretch when cells were treated with a TRPV4 antagonist. TRPV4 regulates ghrelin secretion in response to stretch in the stomach, which may affect body weight.
Collapse
Affiliation(s)
- Shunsuke Hayakawa
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Tatsuya Tanaka
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Ryo Ogawa
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Sunao Ito
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Shuhei Ueno
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Hiroyuki Koyama
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Okubo Tomotaka
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Hiroyuki Sagawa
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Tomohiro Tanaka
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hiroshi Iwakura
- Department of Pharmacotherapeutics, Wakayama Medical University, Kimiidera, Wakayama, Wakayama, Japan
| | - Hiroki Takahashi
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Yoichi Matsuo
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Akira Mitsui
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Masahiro Kimura
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Satoru Takahashi
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Shuji Takiguchi
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| |
Collapse
|
|
25
|
Blazer-Yost BL. Following Ussing's legacy: from amphibian models to mammalian kidney and brain. Am J Physiol Cell Physiol 2022; 323:C1061-C1069. [PMID: 36036449 PMCID: PMC9529261 DOI: 10.1152/ajpcell.00303.2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/17/2022] [Accepted: 08/19/2022] [Indexed: 11/22/2022]
Abstract
Professor Hans H. Ussing (1911-2000) was one of the founding members of the field of epithelial cell biology. He is most famous for the electrophysiological technique that he developed to measure electrogenic ion flux across epithelial tissues. Ussing-style electrophysiology has been applied to multiple tissues and has informed fields as diverse as amphibian biology and medicine. In the latter, this technique has contributed to a basic understanding of maladies such as hypertension, polycystic kidney disease, cystic fibrosis, and diarrheal diseases to mention but a few. In addition to this valuable contribution to biological methods, Prof. Ussing also provided strong evidence for the concept of active transport several years before the elucidation of Na+K+ATPase. In addition, he provided cell biologists with the important concept of polarized epithelia with specific and different transporters found in the apical and basolateral membranes, thus providing these cells with the ability to conduct directional, active and passive transepithelial transport. My studies have used Ussing chamber electrophysiology to study the toad urinary bladder, an amphibian cell line, renal cell lines, and, most recently, choroid plexus cell lines. This technique has formed the basis of our in vitro mechanistic studies that are used in an iterative manner with animal models to better understand disease progress and treatment. I was honored to be invited to deliver the 2022 Hans Ussing Lecture sponsored by the Epithelial Transport Group of the American Physiological Society. This manuscript is a version of the material presented in that lecture.
Collapse
Affiliation(s)
- Bonnie L Blazer-Yost
- Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, Indiana
| |
Collapse
|
|
26
|
Caires R, Garrud TAC, Romero LO, Fernández-Peña C, Vásquez V, Jaggar JH, Cordero-Morales JF. Genetic- and diet-induced ω-3 fatty acid enrichment enhances TRPV4-mediated vasodilation in mice. Cell Rep 2022; 40:111306. [PMID: 36070688 PMCID: PMC9498980 DOI: 10.1016/j.celrep.2022.111306] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 07/05/2022] [Accepted: 08/11/2022] [Indexed: 11/19/2022] Open
Abstract
TRPV4 channel activation in endothelial cells leads to vasodilation, while impairment of TRPV4 activity is implicated in vascular dysfunction. Strategies that increase TRPV4 activity could enhance vasodilation and ameliorate vascular disorders. Here, we show that supplementation with eicosapentaenoic acid (EPA), an ω-3 polyunsaturated fatty acid known to have beneficial cardiovascular effects, increases TRPV4 activity in human endothelial cells of various vascular beds. Mice carrying the C. elegans FAT-1 enzyme, which converts ω-6 to ω-3 polyunsaturated fatty acids, display higher EPA content and increased TRPV4-mediated vasodilation in mesenteric arteries. Likewise, mice fed an EPA-enriched diet exhibit enhanced and prolonged TRPV4-dependent vasodilation in an endothelial cell-specific manner. We also show that EPA supplementation reduces TRPV4 desensitization, which contributes to the prolonged vasodilation. Neutralization of positive charges in the TRPV4 N terminus impairs the effect of EPA on channel desensitization. These findings highlight the beneficial effects of manipulating fatty acid content to enhance TRPV4-mediated vasodilation.
Collapse
Affiliation(s)
- Rebeca Caires
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Tessa A C Garrud
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Luis O Romero
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Integrated Biomedical Sciences Graduate Program, College of Graduate Health Sciences, Memphis, TN 38163, USA
| | - Carlos Fernández-Peña
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Valeria Vásquez
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Jonathan H Jaggar
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Julio F Cordero-Morales
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
| |
Collapse
|
|
27
|
Lapajne L, Rudzitis CN, Cullimore B, Ryskamp D, Lakk M, Redmon SN, Yarishkin O, Krizaj D. TRPV4: Cell type-specific activation, regulation and function in the vertebrate eye. CURRENT TOPICS IN MEMBRANES 2022; 89:189-219. [PMID: 36210149 PMCID: PMC9879314 DOI: 10.1016/bs.ctm.2022.07.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The architecture of the vertebrate eye is optimized for efficient delivery and transduction of photons and processing of signaling cascades downstream from phototransduction. The cornea, lens, retina, vasculature, ciliary body, ciliary muscle, iris and sclera have specialized functions in ocular protection, transparency, accommodation, fluid regulation, metabolism and inflammatory signaling, which are required to enable function of the retina-light sensitive tissue in the posterior eye that transmits visual signals to relay centers in the midbrain. This process can be profoundly impacted by non-visual stimuli such as mechanical (tension, compression, shear), thermal, nociceptive, immune and chemical stimuli, which target these eye regions to induce pain and precipitate vision loss in glaucoma, diabetic retinopathy, retinal dystrophies, retinal detachment, cataract, corneal dysfunction, ocular trauma and dry eye disease. TRPV4, a polymodal nonselective cation channel, integrate non-visual inputs with homeostatic and signaling functions of the eye. The TRPV4 gene is expressed in most if not all ocular tissues, which vary widely with respect to the mechanisms of TRPV4 channel activation, modulation, oligomerization, and participation in protein- and lipid interactions. Under- and overactivation of TRPV4 may affect intraocular pressure, maintenance of blood-retina barriers, lens accommodation, neuronal function and neuroinflammation. Because TRPV4 dysregulation precipitates many pathologies across the anterior and posterior eye, the channel could be targeted to mitigate vision loss.
Collapse
Affiliation(s)
- Luka Lapajne
- Department of Ophthalmology & Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT, United States; Department of Ophthalmology, University Medical Centre, University of Ljubljana, Ljubljana, Slovenia
| | - Christopher N Rudzitis
- Department of Ophthalmology & Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT, United States
| | - Brenan Cullimore
- Department of Ophthalmology & Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT, United States
| | - Daniel Ryskamp
- Department of Ophthalmology & Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT, United States
| | - Monika Lakk
- Department of Ophthalmology & Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT, United States
| | - Sarah N Redmon
- Department of Ophthalmology & Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT, United States
| | - Oleg Yarishkin
- Department of Ophthalmology & Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT, United States
| | - David Krizaj
- Department of Ophthalmology & Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT, United States; Department of Neurobiology, University of Utah, Salt Lake City, UT, United States; Department of Bioengineering, University of Utah, Salt Lake City, UT, United States.
| |
Collapse
|
|
28
|
Hu F, Cao X, Niu C, Wang K. Coassembly of Warm Temperature-Sensitive Transient Receptor Potential Vanilloid (TRPV) 3 and TRPV4 Channel Complexes with Distinct Functional Properties. Mol Pharmacol 2022; 101:390-399. [PMID: 35361697 DOI: 10.1124/molpharm.121.000370] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 03/17/2022] [Indexed: 11/22/2022] Open
Abstract
Heteromeric assembly of temperature-sensitive transient receptor potential (TRP) ion channels has been suggested to underlie the molecular basis of fine-tuning of temperature detection and chemical sensation. However, whether warm temperature-sensitive TRP vanilloid (TRPV) 3 and TRPV4 channels robustly expressed in the skin can form heteromeric assembly remains largely unknown. In this study, we show that TRPV3 and TRPV4 channels can coassemble into functional heterotetrameric channels with distinct properties. Confocal imaging reveals a colocalization and association of TRPV3 and TRPV4 proteins in cell membrane. Coimmunoprecipitation analysis demonstrates a strong protein-protein interaction between TRPV3 and TRPV4 subunits from heterogeneously expressed cells or mouse skin tissues through their C termini but not in TRPV3 knockout tissues. Coexpression of TRPV3 and TRPV4 channels yields a heterotetrameric channel complexes characterized by an intermediate single-channel conductance, distinct activation threshold, and pharmacology. Taken together, our findings demonstrate a heterotetrameric assembly of TRPV3 and TRPV4 channels, which may help explain the role of temperature-sensitive TRPV channels in fine-tuning of environmental detection and sensation in the skin. SIGNIFICANCE STATEMENT: The coassembly of transient receptor potential vanilloid (TRPV) 3 and TRPV4 channel complexes increases the functional diversity within the channel subfamily, which may serve as a molecular basis for fine-tuning of environmental detection and temperature sensation in mammals.
Collapse
Affiliation(s)
- Fang Hu
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao, China (F.H., C.N., K.W.); Department of Neurobiology, Neuroscience Research Institute, Peking University Health Science Center, Beijing, China (X.C.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (K.W.)
| | - Xu Cao
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao, China (F.H., C.N., K.W.); Department of Neurobiology, Neuroscience Research Institute, Peking University Health Science Center, Beijing, China (X.C.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (K.W.)
| | - Canyang Niu
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao, China (F.H., C.N., K.W.); Department of Neurobiology, Neuroscience Research Institute, Peking University Health Science Center, Beijing, China (X.C.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (K.W.)
| | - KeWei Wang
- Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao, China (F.H., C.N., K.W.); Department of Neurobiology, Neuroscience Research Institute, Peking University Health Science Center, Beijing, China (X.C.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (K.W.)
| |
Collapse
|
|
29
|
Calcium–Permeable Channels and Endothelial Dysfunction in Acute Lung Injury. Curr Issues Mol Biol 2022; 44:2217-2229. [PMID: 35678679 PMCID: PMC9164020 DOI: 10.3390/cimb44050150] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/06/2022] [Accepted: 05/10/2022] [Indexed: 11/17/2022] Open
Abstract
The increased permeability of the lung microvascular endothelium is one critical initiation of acute lung injury (ALI). The disruption of vascular-endothelium integrity results in leakiness of the endothelial barrier and accumulation of protein-rich fluid in the alveoli. During ALI, increased endothelial-cell (EC) permeability is always companied by high frequency and amplitude of cytosolic Ca2+ oscillations. Mechanistically, cytosolic calcium oscillations include calcium release from internal stores and calcium entry via channels located in the cell membrane. Recently, numerous publications have shown substantial evidence that calcium-permeable channels play an important role in maintaining the integrity of the endothelium barrier function of the vessel wall in ALI. These novel endothelial signaling pathways are future targets for the treatment of lung injury. This short review focuses on the up-to-date research and provide insight into the contribution of calcium influx via ion channels to the disruption of lung microvascular endothelial-barrier function during ALI.
Collapse
|
|
30
|
Kleene SJ. Regenerative Calcium Currents in Renal Primary Cilia. Front Physiol 2022; 13:894518. [PMID: 35620606 PMCID: PMC9127361 DOI: 10.3389/fphys.2022.894518] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 04/18/2022] [Indexed: 11/13/2022] Open
Abstract
Polycystic kidney disease (PKD) is a leading cause of end-stage renal disease. PKD arises from mutations in proteins, one a Ca2+-conducting channel, expressed in the primary cilia of renal epithelial cells. A common hypothesis is that Ca2+ entering through ciliary ion channels may reduce cystogenesis. The cilia have at least two Ca2+-conducting channels: polycystin-2 (PC2) and TRPV4 (transient receptor potential (TRP) cation channel, subfamily V, member 4), but how substantially they can increase intraciliary Ca2+ is unknown. By recording channel activities in isolated cilia, conditions are identified under which the channels can increase free Ca2+ within the cilium by at least 500-fold through regenerative (positive-feedback) signaling. Ca2+ that has entered through a channel can activate the channel internally, which increases the Ca2+ influx, and so on. Regenerative signaling is favored when the concentration of the Ca2+ buffer is reduced or when a slower buffer is used. Under such conditions, the Ca2+ that enters the cilium through a single PC2 channel is sufficient to almost fully activate that same channel. Regenerative signaling is not detectable with reduced external Ca2+. Reduced buffering also allows regenerative signaling through TRPV4 channels, but not through TRPM4 (TRP subfamily M, member 4) channels, which are activated by Ca2+ but do not conduct it. On a larger scale, Ca2+ that enters through TRPV4 channels can cause secondary activation of PC2 channels. I discuss the likelihood of regenerative ciliary Ca2+ signaling in vivo, a possible mechanism for its activation, and how it might relate to cystogenesis.
Collapse
Affiliation(s)
- Steven J. Kleene
- Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, OH, United States
| |
Collapse
|
|
31
|
Role of Ion Channel Remodeling in Endothelial Dysfunction Induced by Pulmonary Arterial Hypertension. Biomolecules 2022; 12:biom12040484. [PMID: 35454073 PMCID: PMC9031742 DOI: 10.3390/biom12040484] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/14/2022] [Accepted: 03/15/2022] [Indexed: 12/12/2022] Open
Abstract
Endothelial dysfunction is a key player in advancing vascular pathology in pulmonary arterial hypertension (PAH), a disease essentially characterized by intense remodeling of the pulmonary vasculature, vasoconstriction, endothelial dysfunction, inflammation, oxidative stress, and thrombosis in situ. These vascular features culminate in an increase in pulmonary vascular resistance, subsequent right heart failure, and premature death. Over the past years, there has been a great development in our understanding of pulmonary endothelial biology related to the genetic and molecular mechanisms that modulate the endothelial response to direct or indirect injury and how their dysregulation can promote PAH pathogenesis. Ion channels are key regulators of vasoconstriction and proliferative/apoptotic phenotypes; however, they are poorly studied at the endothelial level. The current review will describe and categorize different expression, functions, regulation, and remodeling of endothelial ion channels (K+, Ca2+, Na+, and Cl− channels) in PAH. We will focus on the potential pathogenic role of ion channel deregulation in the onset and progression of endothelial dysfunction during the development of PAH and its potential therapeutic role.
Collapse
|
|
32
|
Chen Y, Petrova RS, Qiu C, Donaldson PJ. -Intracellular hydrostatic pressure regulation in the bovine lens: a role in the regulation of lens optics? Am J Physiol Regul Integr Comp Physiol 2022; 322:R263-R279. [PMID: 35107027 DOI: 10.1152/ajpregu.00309.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The optical properties of the bovine lens have been shown to be actively maintained by an internal microcirculation system. In the mouse lens, this water transport through gap junction channels generates an intracellular hydrostatic pressure gradient, which is subjected to a dual feedback regulation that is mediated by the reciprocal modulation of the transient receptor potential vanilloid channels, TRPV1 and TRPV4. Here we test whether a similar feedback regulation of pressure exists in the bovine lens, and whether it regulates overall lens optics. Lens pressure was measured using a microelectrode/pico-injector-based pressure measurement system, and lens optics were monitored in organ cultured lenses using a laser ray tracing system. Like the mouse, the bovine lenses exhibited a similar pressure gradient (0 to 340 mmHg). Activation of TRPV1 with capsaicin caused a biphasic increase in surface pressure, while activation of TRPV4 with GSK1016790A caused a biphasic decrease in pressure. These biphasic responses were abolished if lenses were pre-incubated with either the TRPV1 inhibitor A-889425, or the TRPV4 inhibitor HC-067047. While modulation of lens pressure by TRPV1 and TRPV4 had minimal effects on lens power and overall vision quality, the changes in lens pressure did induce opposing changes to lens geometry and GRIN that effectively kept lens power constant. Hence, our results suggest that the TRPV1/4 mediated feedback control of lens hydrostatic pressure operates to ensure that any fluctuations in lens water transport, and consequently water content, do not result in changes in lens power and therefore overall vision quality.
Collapse
Affiliation(s)
- Yadi Chen
- Department of Physiology, School of Medical Sciences, New Zealand Eye Centre, University of Auckland, New Zealand
| | - Rosica S Petrova
- Department of Physiology, School of Medical Sciences, New Zealand Eye Centre, University of Auckland, New Zealand
| | - Chen Qiu
- Department of Physiology, School of Medical Sciences, New Zealand Eye Centre, University of Auckland, New Zealand
| | - Paul J Donaldson
- Department of Physiology, School of Medical Sciences, New Zealand Eye Centre, University of Auckland, New Zealand
| |
Collapse
|
|
33
|
Abstract
The alveolo-capillary barrier is relatively impermeable, and facilitates gas exchange via the large alveolar surface in the lung. Disruption of alveolo-capillary barrier leads to accumulation of edema fluid in lung injury. Studies in animal models of various forms of lung injury provide evidence that TRPV4 channels play a critical role in disruption of the alveolo-capillary barrier and pathogenesis of lung injury. TRPV4 channels from capillary endothelial cells, alveolar epithelial cells, and immune cells have been implicated in the pathogenesis of lung injury. Recent studies in endothelium-specific TRPV4 knockout mice point to a central role for endothelial TRPV4 channels in lung injury. In this chapter, we review the findings on the pathological roles of endothelial TRPV4 channels in different forms of lung injury and future directions for further investigation.
Collapse
|
|
34
|
Adapala RK, Katari V, Teegala LR, Thodeti S, Paruchuri S, Thodeti CK. TRPV4 Mechanotransduction in Fibrosis. Cells 2021; 10:cells10113053. [PMID: 34831281 PMCID: PMC8619244 DOI: 10.3390/cells10113053] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/29/2021] [Accepted: 11/04/2021] [Indexed: 12/11/2022] Open
Abstract
Fibrosis is an irreversible, debilitating condition marked by the excessive production of extracellular matrix and tissue scarring that eventually results in organ failure and disease. Differentiation of fibroblasts to hypersecretory myofibroblasts is the key event in fibrosis. Although both soluble and mechanical factors are implicated in fibroblast differentiation, much of the focus is on TGF-β signaling, but to date, there are no specific drugs available for the treatment of fibrosis. In this review, we describe the role for TRPV4 mechanotransduction in cardiac and lung fibrosis, and we propose TRPV4 as an alternative therapeutic target for fibrosis.
Collapse
Affiliation(s)
- Ravi K. Adapala
- Department of Physiology and Pharmacology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (R.K.A.); (V.K.); (L.R.T.); (S.P.)
| | - Venkatesh Katari
- Department of Physiology and Pharmacology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (R.K.A.); (V.K.); (L.R.T.); (S.P.)
| | - Lakshminarayan Reddy Teegala
- Department of Physiology and Pharmacology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (R.K.A.); (V.K.); (L.R.T.); (S.P.)
| | | | - Sailaja Paruchuri
- Department of Physiology and Pharmacology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (R.K.A.); (V.K.); (L.R.T.); (S.P.)
| | - Charles K. Thodeti
- Department of Physiology and Pharmacology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (R.K.A.); (V.K.); (L.R.T.); (S.P.)
- Correspondence:
| |
Collapse
|
|
35
|
Kuwashima Y, Yanagawa M, Abe M, Hiroshima M, Ueda M, Arita M, Sako Y. Comparative Analysis of Single-Molecule Dynamics of TRPV1 and TRPV4 Channels in Living Cells. Int J Mol Sci 2021; 22:ijms22168473. [PMID: 34445178 PMCID: PMC8395219 DOI: 10.3390/ijms22168473] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 07/28/2021] [Accepted: 08/03/2021] [Indexed: 12/27/2022] Open
Abstract
TRPV1 and TRPV4, members of the transient receptor potential vanilloid family, are multimodal ion channels activated by various stimuli, including temperature and chemicals. It has been demonstrated that TRPV channels function as tetramers; however, the dynamics of the diffusion, oligomerization, and endocytosis of these channels in living cells are unclear. Here we undertook single-molecule time-lapse imaging of TRPV1 and TRPV4 in HEK 293 cells. Differences were observed between TRPV1 and TRPV4 before and after agonist stimulation. In the resting state, TRPV4 was more likely to form higher-order oligomers within immobile membrane domains than TRPV1. TRPV1 became immobile after capsaicin stimulation, followed by its gradual endocytosis. In contrast, TRPV4 was rapidly internalized upon stimulation with GSK1016790A. The selective loss of immobile higher-order oligomers from the cell surface through endocytosis increased the proportion of the fast-diffusing state for both subtypes. With the increase in the fast state, the association rate constants of TRPV1 and TRPV4 increased, regenerating the higher-order oligomers. Our results provide a possible mechanism for the different rates of endocytosis of TRPV1 and TRPV4 based on the spatial organization of the higher-order structures of the two TRPV channels.
Collapse
Affiliation(s)
- Yutaro Kuwashima
- Cellular Informatics Laboratory, RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako 351-0198, Saitama, Japan; (Y.K.); (M.A.); (M.H.)
- Division of Physiological Chemistry and Metabolism, Keio University Faculty of Pharmacy, Tokyo 105-0011, Japan;
| | - Masataka Yanagawa
- Cellular Informatics Laboratory, RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako 351-0198, Saitama, Japan; (Y.K.); (M.A.); (M.H.)
- Japan Science and Technology Agency (JST), PRESTO, 4-1-8, Honcho, Kawaguchi 332-0012, Saitama, Japan
- Correspondence: (M.Y.); (Y.S.)
| | - Mitsuhiro Abe
- Cellular Informatics Laboratory, RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako 351-0198, Saitama, Japan; (Y.K.); (M.A.); (M.H.)
| | - Michio Hiroshima
- Cellular Informatics Laboratory, RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako 351-0198, Saitama, Japan; (Y.K.); (M.A.); (M.H.)
- Laboratory for Cell Signaling Dynamics, RIKEN Center for Biosystems Dynamics Research (BDR), 6-2-3, Furuedai, Suita 565-0874, Osaka, Japan;
| | - Masahiro Ueda
- Laboratory for Cell Signaling Dynamics, RIKEN Center for Biosystems Dynamics Research (BDR), 6-2-3, Furuedai, Suita 565-0874, Osaka, Japan;
- Laboratory of Single Molecule Biology, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita 565-0871, Osaka, Japan
| | - Makoto Arita
- Division of Physiological Chemistry and Metabolism, Keio University Faculty of Pharmacy, Tokyo 105-0011, Japan;
- Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama 230-0045, Kanagawa, Japan
- Cellular and Molecular Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama 230-0045, Kanagawa, Japan
| | - Yasushi Sako
- Cellular Informatics Laboratory, RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako 351-0198, Saitama, Japan; (Y.K.); (M.A.); (M.H.)
- Correspondence: (M.Y.); (Y.S.)
| |
Collapse
|
|
36
|
Sun W, Luo Y, Zhang F, Tang S, Zhu T. Involvement of TRP Channels in Adipocyte Thermogenesis: An Update. Front Cell Dev Biol 2021; 9:686173. [PMID: 34249940 PMCID: PMC8264417 DOI: 10.3389/fcell.2021.686173] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 06/02/2021] [Indexed: 01/27/2023] Open
Abstract
Obesity prevalence became a severe global health problem and it is caused by an imbalance between energy intake and expenditure. Brown adipose tissue (BAT) is a major site of mammalian non-shivering thermogenesis or energy dissipation. Thus, modulation of BAT thermogenesis might be a promising application for body weight control and obesity prevention. TRP channels are non-selective calcium-permeable cation channels mainly located on the plasma membrane. As a research focus, TRP channels have been reported to be involved in the thermogenesis of adipose tissue, energy metabolism and body weight regulation. In this review, we will summarize and update the recent progress of the pathological/physiological involvement of TRP channels in adipocyte thermogenesis. Moreover, we will discuss the potential of TRP channels as future therapeutic targets for preventing and combating human obesity and related-metabolic disorders.
Collapse
Affiliation(s)
- Wuping Sun
- Department of Pain Medicine and Shenzhen Municipal Key Laboratory for Pain Medicine, Shenzhen Nanshan People's Hospital and The 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
| | - Yixuan Luo
- Department of Cardiovascular Surgery, Shenzhen Nanshan People's Hospital and The 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
| | - Fei Zhang
- Department of Cardiovascular Surgery, Shenzhen Nanshan People's Hospital and The 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
| | - Shuo Tang
- Department of Orthopaedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Tao Zhu
- Department of Respiratory Medicine, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
37
|
Chen M, Li X. Role of TRPV4 channel in vasodilation and neovascularization. Microcirculation 2021; 28:e12703. [PMID: 33971061 DOI: 10.1111/micc.12703] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 05/02/2021] [Indexed: 12/12/2022]
Abstract
The transient receptor potential vanilloid type 4 (TRPV4) channel, a Ca2+ -permeable nonselective cation channel, is widely distributed in the circulatory system, particularly in vascular endothelial cells (ECs) and smooth muscle cells (SMCs). The TRPV4 channel is activated by various endogenous and exogenous stimuli, including shear stress, low intravascular pressure, and arachidonic acid. TRPV4 has a role in mediating vascular tone and arterial blood pressure. The activation of the TRPV4 channel induces Ca2+ influx, thereby resulting in endothelium-dependent hyperpolarization and SMC relaxation through SKCa and IKCa activation on ECs or through BKCa activation on SMCs. Ca2+ binds to calmodulin, which leads to the production of nitric oxide, causing vasodilation. Furthermore, the TRPV4 channel plays an important role in angiogenesis and arteriogenesis and is critical for tumor angiogenesis and growth, since it promotes or inhibits the development of various types of cancer. The TRPV4 channel is involved in the active growth of collateral arteries induced by flow shear stress, which makes it a promising therapeutic target in the occlusion or stenosis of the main arteries. In this review, we explore the role and the potential mechanism of action of the TRPV4 channel in the regulation of vascular tone and in the induction of neovascularization to provide a reference for future research.
Collapse
Affiliation(s)
- Miao Chen
- Department of Hand and Foot Surgery, The First Hospital of Jilin University, Changchun, China
| | - Xiucun Li
- Department of Hand and Foot Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Anatomy and Histoembryology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China
| |
Collapse
|
|
38
|
Liu L, Guo M, Lv X, Wang Z, Yang J, Li Y, Yu F, Wen X, Feng L, Zhou T. Role of Transient Receptor Potential Vanilloid 4 in Vascular Function. Front Mol Biosci 2021; 8:677661. [PMID: 33981725 PMCID: PMC8107436 DOI: 10.3389/fmolb.2021.677661] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 04/06/2021] [Indexed: 12/19/2022] Open
Abstract
Transient receptor potential vanilloid 4 (TRPV4) channels are widely expressed in systemic tissues and can be activated by many stimuli. TRPV4, a Ca2+-permeable cation channel, plays an important role in the vasculature and is implicated in the regulation of cardiovascular homeostasis processes such as blood pressure, vascular remodeling, and pulmonary hypertension and edema. Within the vasculature, TRPV4 channels are expressed in smooth muscle cells, endothelial cells, and perivascular nerves. The activation of endothelial TRPV4 contributes to vasodilation involving nitric oxide, prostacyclin, and endothelial-derived hyperpolarizing factor pathways. TRPV4 activation also can directly cause vascular smooth muscle cell hyperpolarization and vasodilation. In addition, TRPV4 activation can evoke constriction in some specific vascular beds or under some pathological conditions. TRPV4 participates in the control of vascular permeability and vascular damage, particularly in the lung capillary endothelial barrier and lung injury. It also participates in vascular remodeling regulation mainly by controlling vasculogenesis and arteriogenesis. This review examines the role of TRPV4 in vascular function, particularly in vascular dilation and constriction, vascular permeability, vascular remodeling, and vascular damage, along with possible mechanisms, and discusses the possibility of targeting TRPV4 for therapy.
Collapse
Affiliation(s)
- Liangliang Liu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Mengting Guo
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Xiaowang Lv
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Zhiwei Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Jigang Yang
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Yanting Li
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Fan Yu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Xin Wen
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Lei Feng
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Tingting Zhou
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| |
Collapse
|
|
39
|
Pacheco G, Oliveira AP, Noleto IRSG, Araújo AK, Lopes ALF, Sousa FBM, Chaves LS, Alves EHP, Vasconcelos DFP, Araujo AR, Nicolau LD, Magierowski M, Medeiros JVR. Activation of transient receptor potential vanilloid channel 4 contributes to the development of ethanol-induced gastric injury in mice. Eur J Pharmacol 2021; 902:174113. [PMID: 33901460 DOI: 10.1016/j.ejphar.2021.174113] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 04/09/2021] [Accepted: 04/19/2021] [Indexed: 02/07/2023]
Abstract
The transient receptor potential vanilloid channel 4 (TRPV4) is associated with the development of several pathologies, particularly gastric disorders. However, there are no studies associating this receptor with the pathophysiology of gastric erosions. The aim of this study was to investigate the role of TRPV4 in the development of ethanol-induced gastric damage in vivo. Gastric lesions were induced by ethanol in Swiss mice pretreated with TRPV4 antagonists, GSK2193874 (0.1; 0.3 and 0.9 mg/kg) or Ruthenium red (0.03; 0.1 or 0.3 mg/kg) or its agonist, GSK1016790A (0.9 mg/kg). Gastric mucosal samples were taken for histopathology, immunohistochemistry, atomic force microscopy and evaluation of antioxidant parameters. The gastric mucus content and TRPV4 mRNA expression were analyzed. Ethanol exposure induced upregulation of gastric mRNA and protein expression of TRPV4. TRPV4 blockade promoted gastroprotection against ethanol-induced injury on macro- and microscopic levels, leading to reduced hemorrhage, cell loss and edema and enhanced gastric mucosal integrity. Moreover, an increase in superoxide dismutase (SOD) and glutathione (GSH) activity was observed, followed by a decrease in malondialdehyde (MDA) levels. TRPV4 blockade during alcohol challenge reestablished gastric mucus content. The combination of TRPV4 agonist and ethanol revealed macroscopic exacerbation of gastric damage area. Our results confirmed the association of TRPV4 with the development of gastric injury, showing the importance of this receptor for further investigations in the field of gastrointestinal pathophysiology and pharmacology.
Collapse
Affiliation(s)
- Gabriella Pacheco
- Biotechnology and Biodiversity Center Research (BIOTEC), Post-graduation Program in Biotechnology, Federal University of the Parnaíba Delta (UFDPar), Parnaíba, PI, Brazil
| | - Ana P Oliveira
- The Northeastern Biotechnology Network (RENORBIO), Federal University of Piauí (UFPI), Teresina, PI, Brazil
| | - Isabela R S G Noleto
- The Northeastern Biotechnology Network (RENORBIO), Federal University of Piauí (UFPI), Teresina, PI, Brazil
| | - Andreza K Araújo
- Biotechnology and Biodiversity Center Research (BIOTEC), Post-graduation Program in Biotechnology, Federal University of the Parnaíba Delta (UFDPar), Parnaíba, PI, Brazil
| | - André L F Lopes
- Biotechnology and Biodiversity Center Research (BIOTEC), Post-graduation Program in Biotechnology, Federal University of the Parnaíba Delta (UFDPar), Parnaíba, PI, Brazil
| | - Francisca B M Sousa
- The Northeastern Biotechnology Network (RENORBIO), Federal University of Piauí (UFPI), Teresina, PI, Brazil
| | - Letícia S Chaves
- Biotechnology and Biodiversity Center Research (BIOTEC), Post-graduation Program in Biotechnology, Federal University of the Parnaíba Delta (UFDPar), Parnaíba, PI, Brazil
| | - Even H P Alves
- Biotechnology and Biodiversity Center Research (BIOTEC), Post-graduation Program in Biotechnology, Federal University of the Parnaíba Delta (UFDPar), Parnaíba, PI, Brazil
| | - Daniel F P Vasconcelos
- Biotechnology and Biodiversity Center Research (BIOTEC), Post-graduation Program in Biotechnology, Federal University of the Parnaíba Delta (UFDPar), Parnaíba, PI, Brazil; The Northeastern Biotechnology Network (RENORBIO), Federal University of Piauí (UFPI), Teresina, PI, Brazil
| | - Alyne R Araujo
- Biotechnology and Biodiversity Center Research (BIOTEC), Post-graduation Program in Biotechnology, Federal University of the Parnaíba Delta (UFDPar), Parnaíba, PI, Brazil
| | - LucasA D Nicolau
- Biotechnology and Biodiversity Center Research (BIOTEC), Post-graduation Program in Biotechnology, Federal University of the Parnaíba Delta (UFDPar), Parnaíba, PI, Brazil
| | - Marcin Magierowski
- Gaseous Mediators and Experimental Gastroenterology Laboratory, Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
| | - Jand Venes R Medeiros
- Biotechnology and Biodiversity Center Research (BIOTEC), Post-graduation Program in Biotechnology, Federal University of the Parnaíba Delta (UFDPar), Parnaíba, PI, Brazil; The Northeastern Biotechnology Network (RENORBIO), Federal University of Piauí (UFPI), Teresina, PI, Brazil.
| |
Collapse
|
|
40
|
Rajan S, Schremmer C, Weber J, Alt P, Geiger F, Dietrich A. Ca 2+ Signaling by TRPV4 Channels in Respiratory Function and Disease. Cells 2021; 10:cells10040822. [PMID: 33917551 PMCID: PMC8067475 DOI: 10.3390/cells10040822] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 03/23/2021] [Accepted: 04/04/2021] [Indexed: 12/14/2022] Open
Abstract
Members of the transient receptor potential (TRP) superfamily are broadly expressed in our body and contribute to multiple cellular functions. Most interestingly, the fourth member of the vanilloid family of TRP channels (TRPV4) serves different partially antagonistic functions in the respiratory system. This review highlights the role of TRPV4 channels in lung fibroblasts, the lung endothelium, as well as the alveolar and bronchial epithelium, during physiological and pathophysiological mechanisms. Data available from animal models and human tissues confirm the importance of this ion channel in cellular signal transduction complexes with Ca2+ ions as a second messenger. Moreover, TRPV4 is an excellent therapeutic target with numerous specific compounds regulating its activity in diseases, like asthma, lung fibrosis, edema, and infections.
Collapse
|
|
41
|
Ottolini M, Sonkusare SK. The Calcium Signaling Mechanisms in Arterial Smooth Muscle and Endothelial Cells. Compr Physiol 2021; 11:1831-1869. [PMID: 33792900 PMCID: PMC10388069 DOI: 10.1002/cphy.c200030] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The contractile state of resistance arteries and arterioles is a crucial determinant of blood pressure and blood flow. Physiological regulation of arterial contractility requires constant communication between endothelial and smooth muscle cells. Various Ca2+ signals and Ca2+ -sensitive targets ensure dynamic control of intercellular communications in the vascular wall. The functional effect of a Ca2+ signal on arterial contractility depends on the type of Ca2+ -sensitive target engaged by that signal. Recent studies using advanced imaging methods have identified the spatiotemporal signatures of individual Ca2+ signals that control arterial and arteriolar contractility. Broadly speaking, intracellular Ca2+ is increased by ion channels and transporters on the plasma membrane and endoplasmic reticular membrane. Physiological roles for many vascular Ca2+ signals have already been confirmed, while further investigation is needed for other Ca2+ signals. This article focuses on endothelial and smooth muscle Ca2+ signaling mechanisms in resistance arteries and arterioles. We discuss the Ca2+ entry pathways at the plasma membrane, Ca2+ release signals from the intracellular stores, the functional and physiological relevance of Ca2+ signals, and their regulatory mechanisms. Finally, we describe the contribution of abnormal endothelial and smooth muscle Ca2+ signals to the pathogenesis of vascular disorders. © 2021 American Physiological Society. Compr Physiol 11:1831-1869, 2021.
Collapse
Affiliation(s)
- Matteo Ottolini
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia, USA
| | - Swapnil K Sonkusare
- Department of Pharmacology, University of Virginia, Charlottesville, Virginia, USA.,Department of Molecular Physiology & Biological Physics, University of Virginia, Charlottesville, Virginia, USA.,Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA
| |
Collapse
|
|
42
|
Xu X, Goyal N, Costell MH, Roethke T, James CH, Thorneloe KS, Patterson J, Stoy P, Goodman K, Sprecher DL, Behm DJ. Identification of a Human Whole Blood-Based Endothelial Cell Impedance Assay for Assessing Clinical Transient Receptor Potential Vanilloid 4 Target Engagement Ex Vivo. J Pharmacol Exp Ther 2021; 376:436-443. [PMID: 33376150 DOI: 10.1124/jpet.120.000307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 12/23/2020] [Indexed: 11/22/2022] Open
Abstract
Transient receptor potential vanilloid 4 (TRPV4) channels expressed on pulmonary endothelial cells are activated by elevated pulmonary vascular pressure, resulting in endothelial shape change, pulmonary barrier disruption, and edema. As such, TRPV4 blocker GSK2798745 was recently investigated in phase I/IIa trials to reduce pulmonary edema caused by heart failure (HF). In the absence of a suitable TRPV4 target engagement biomarker, we hypothesized that an ex vivo assay could be used to predict pharmacological activity at the intended site of action (endothelial cells) of subjects. In this assay, the ability of GSK2798745 to block TRPV4 agonist GSK1016790-induced impendence reduction in human umbilical vein endothelial cells (HUVECs) in the presence of human whole blood was assessed. Blood from healthy volunteers drawn 1-12 hours after single or repeated dose of GSK2798745 (5 mg) inhibited GSK1016790-induced impedance reduction by ≥85%. Similarly, blood samples from 16 subjects with HF dosed with GSK2798745 (2.4 mg) inhibited GSK1016790-induced HUVEC impedance reduction by ≥58% 1-24 hours after single dosing and ≥78% 1-24 hours after 7 days of repeated dosing. No inhibition was detected using blood from placebo subjects. Using matched GSK2798745 plasma levels, a pharmacokinetic/pharmacodynamic (PK/PD) relationship was calculated as 2.9 nM IC50, consistent with the 6.5 nM IC50 of GSK2798745 obtained from a rat in vivo PK/PD model of pulmonary edema after correcting for rat-to-human differences. These results indicate that circulating levels of GSK2798745 in the recently completed phase I/IIa trials were sufficient to block TRPV4 in lung vascular endothelial cells to a large extent, supporting this dosing regimen for assessing efficacy in HF. SIGNIFICANCE STATEMENT: In the absence of a suitable target engagement biomarker, we developed an ex vivo assay to predict the pharmacological activity of the transient receptor potential vanilloid 4 (TRPV4) blocker GSK2798745 in healthy volunteers and subjects with heart failure (HF) from phase I/IIa trials. The potency values from the ex vivo assay were consistent with those predicted from a rat in vivo pharmacokinetic/pharmacodynamic model of pulmonary edema, strongly suggesting that circulating levels of GSK2798745 were sufficient to robustly block TRPV4, supporting use of GSK2798745 for assessing efficacy in HF.
Collapse
|
|
43
|
Jentsch Matias de Oliveira JR, Amorim MA, André E. The role of TRPA1 and TRPV4 channels in bronchoconstriction and plasma extravasation in airways of rats treated with captopril. Pulm Pharmacol Ther 2021; 65:102004. [PMID: 33610768 DOI: 10.1016/j.pupt.2021.102004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 02/05/2021] [Accepted: 02/13/2021] [Indexed: 12/16/2022]
Abstract
Angiotensin-converting enzyme inhibitors (ACEis) may cause adverse airway events, such as cough and angioedema, due to a reduction in bradykinin breakdown and consequent activation of bradykinin type 2 receptor (B2 receptor). Recent studies have shown that bradykinin can also sensitize pro-inflammatory receptors such as the transient receptor potential ankyrin 1 (TRPA1) and vanilloid 4 (TRPV4), which are implicated in several inflammatory airway diseases. Based on these considerations, the aim of this study was to understand the role of TRPA1 and TRPV4 channels in the bronchoconstrictive response and plasma extravasation in the trachea of rats pretreated with captopril. Using methods to detect alterations in airway resistance and plasma extravasation, we found that intravenous (i.v.) administration of bradykinin (0.03-0.3 μmol/kg, B2 receptor agonist), allyl isothiocyanate (100-1000 μmol/kg, TRPA1 agonist) or GSK1016790A (0.01-0.1 μmol/kg, TRPV4 agonist), but not des-arg9-bradykinin (DABK; 100-300 μmol/kg, B1 receptor agonist), induced bronchoconstriction in anaesthetized rats. In doses that did not cause significant bronchoconstriction, bradykinin (0.03 μmol/kg) or allyl isothiocyanate (100 μmol/kg), but not GSK1016790A (0.01 μmol/kg) or DABK (300 μmol/kg) induced an increased bronchoconstrictive response in rats pretreated with captopril (2.5 mg/kg, i.v.). On the other hand, in rats pretreated with captopril (5 mg/kg, i.v.), an increased bronchoconstrictive response to GSK1016790A (0.01 μmol/kg) was observed. The bronchoconstrictive response induced by bradykinin in captopril-pretreated rats was inhibited by intratracheal treatment (i.t.) with HC030031 (300 μg/50 μl; 36 ± 9%) or HC067047 (300 μg/50 μl; 35.1 ± 16%), for TRPA1 and TRPV4 antagonists, respectively. However, the co-administration of both antagonists did not increase this inhibition. The bronchoconstriction induced by allyl isothiocyanate in captopril-pretreated rats (2.5 mg/kg) was inhibited (58.3 ± 8%) by the B2 receptor antagonist HOE140 (10 nmol/50 μl, i.t.). Similarly, the bronchoconstriction induced by GSK1016790A in captopril-pretreated rats (5 mg/kg) was also inhibited (84.2 ± 4%) by HOE140 (10 nmol/50 μl, i.t.). Furthermore, the plasma extravasation induced by captopril on the trachea of rats was inhibited by pretreatment with HC030031 (47.2 ± 8%) or HC067047 (38.9 ± 8%). Collectively, these findings support the hypothesis that TRPA1 and TRPV4, via a B2 receptor activation-dependent pathway, are involved in the plasma extravasation and bronchoconstriction induced by captopril, making them possible pharmacological targets to prevent or remediate ACEi-induced adverse respiratory reactions.
Collapse
Affiliation(s)
| | | | - Eunice André
- Department of Pharmacology, Federal University of Paraná, Curitiba, Brazil.
| |
Collapse
|
|
44
|
Abstract
Members of the transient receptor potential (TRP) channels that are expressed in the kidney have gained prominence in recent years following discoveries of their role in maintaining the integrity of the filtration barrier, regulating tubular reabsorption of Ca2+ and Mg2+, and sensing osmotic stimuli. Furthermore, evidence has linked mutations in TRP channels to kidney disease pathophysiological mechanisms, including focal segmental glomerulosclerosis, disturbances in Mg2+ homeostasis, and polycystic kidney disease. Several subtypes of TRP channels are expressed in the renal vasculature, from preglomerular arteries and arterioles to the descending vasa recta. Although investigations on the physiological and pathological significance of renal vascular TRP channels are sparse, studies on isolated vessels and cells have suggested their involvement in renal vasoregulation. Renal blood flow (RBF) is an essential determinant of kidney function, including glomerular filtration, water and solute reabsorption, and waste product excretion. Functional alterations in ion channels that are expressed in the endothelium and smooth muscle of renal vessels can modulate renal vascular resistance, arterial pressure, and RBF. Hence, renal vascular TRP channels are potential therapeutic targets for the treatment of kidney disease. This review summarizes the current knowledge of TRP channel expression in renal vasculature and their role in controlling kidney function in health and disease.
TRP channels are widely distributed in mammalian kidneys in glomerular, tubular, and vascular cells. TRPC and TRPV channels are functionally expressed in afferent arterioles. TRPC4 may regulate Ca2+ signaling in the descending vasa recta. Smooth muscle, endothelial, and pericyte TRP channels may participate in signal transduction mechanisms. TRP channels underlie renal autoregulation and regional kidney perfusion in health and disease.
Collapse
Affiliation(s)
- Praghalathan Kanthakumar
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Adebowale Adebiyi
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States
| |
Collapse
|
|
45
|
Beddek K, Raffin F, Borgel D, Saller F, Riccobono D, Bobe R, Boittin F. TRPV4 channel activation induces the transition of venous and arterial endothelial cells toward a pro-inflammatory phenotype. Physiol Rep 2021; 9:e14613. [PMID: 33512067 PMCID: PMC7845413 DOI: 10.14814/phy2.14613] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 09/20/2020] [Accepted: 09/22/2020] [Indexed: 11/24/2022] Open
Abstract
The Transient Receptor Potential Vanilloid 4 (TRPV4) of endothelial cells contributes to many important functions including the regulation of Ca2+ homeostasis, cell volume, endothelial barrier permeability, and smooth muscle tone. However, its role in the transition of endothelial cells toward a pro-inflammatory phenotype has not been studied so far. Using both arterial and venous endothelial cells, we first show that the pharmacological activation of TRPV4 channels with GSK1016790A, a potent TRPV4 agonist, triggers robust and sustained Ca2+ increases, which are blocked by both TRPV4 antagonists HC067047 and RN9893. TRPV4 activation also triggers the actin cytoskeleton and adherens junction (VE-Cadherin) rearrangement in both arterial and venous endothelial cells and leads to rapid decreases of trans-endothelial electrical resistance. In addition to its effect on endothelial barrier integrity, TRPV4 activation selectively increases ICAM-1 surface expression in arterial and venous endothelial cells, due to the stimulation of ICAM-1 gene expression through the NF-κB transcription factor. TRPV4 channel activation also induced apoptosis of venous and arterial endothelial cells, while TRPV4 blockade reduced apoptosis, even in the absence of TRPV4 activation. As altered barrier integrity, increased adhesion molecule expression and apoptosis are hallmarks of the pro-inflammatory state of endothelial cells, our results indicate that TRPV4 channel activity can induce the transition of both venous and arterial endothelial cells toward a pro-inflammatory phenotype.
Collapse
Affiliation(s)
- Kathia Beddek
- INSERM Unité Mixte de Recherche‐Santé 1176Université Paris‐SudUniversité Paris‐SaclayLe Kremlin‐BicêtreFrance
| | - Florent Raffin
- Département des Plateformesunité Analyses BiologiquesIRBA (Institut de Recherche Biomédicale des Armées)Brétigny‐sur‐OrgeFrance
| | - Delphine Borgel
- INSERM Unité Mixte de Recherche‐Santé 1176Université Paris‐SudUniversité Paris‐SaclayLe Kremlin‐BicêtreFrance
| | - François Saller
- INSERM Unité Mixte de Recherche‐Santé 1176Université Paris‐SudUniversité Paris‐SaclayLe Kremlin‐BicêtreFrance
| | - Diane Riccobono
- Département Effets Biologiques des Rayonnementsunité de RadiobiologieIRBA (Institut de Recherche Biomédicale des Armées)Brétigny‐sur‐OrgeFrance
| | - Régis Bobe
- INSERM Unité Mixte de Recherche‐Santé 1176Université Paris‐SudUniversité Paris‐SaclayLe Kremlin‐BicêtreFrance
| | - François‐Xavier Boittin
- Département Effets Biologiques des Rayonnementsunité de RadiobiologieIRBA (Institut de Recherche Biomédicale des Armées)Brétigny‐sur‐OrgeFrance
| |
Collapse
|
|
46
|
Ji C, McCulloch CA. TRPV4 integrates matrix mechanosensing with Ca 2+ signaling to regulate extracellular matrix remodeling. FEBS J 2020; 288:5867-5887. [PMID: 33300268 DOI: 10.1111/febs.15665] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 11/23/2020] [Indexed: 12/23/2022]
Abstract
In healthy connective tissues, mechanosensors trigger the generation of Ca2+ signals, which enable cells to maintain the structure of the fibrillar collagen matrix through actomyosin contractile forces. Transient receptor potential vanilloid type 4 (TRPV4) is a mechanosensitive Ca2+ -permeable channel that, when expressed in cell-matrix adhesions of the plasma membrane, regulates extracellular matrix (ECM) remodeling. In high prevalence disorders such as fibrosis and tumor metastasis, dysregulated matrix remodeling is associated with disruptions of Ca2+ homeostasis and TRPV4 function. Here, we consider that ECM polymers transmit cell-activating mechanical signals to TRPV4 in cell adhesions. When activated, TRPV4 regulates fibrillar collagen remodeling, thereby altering the mechanical properties of the ECM. In this review, we integrate functionally connected processes of matrix remodeling to highlight how TRPV4 in cell adhesions and matrix mechanics are reciprocally regulated through Ca2+ signaling.
Collapse
Affiliation(s)
- Chenfan Ji
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, ON, Canada
| | | |
Collapse
|
|
47
|
Zubcevic L. Temperature‐sensitive transient receptor potential vanilloid channels: structural insights into ligand‐dependent activation. Br J Pharmacol 2020; 179:3542-3559. [DOI: 10.1111/bph.15310] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 10/19/2020] [Accepted: 10/27/2020] [Indexed: 12/15/2022] Open
Affiliation(s)
- Lejla Zubcevic
- Department of Biochemistry and Molecular Biology The University of Kansas School of Medicine Kansas City KS USA
| |
Collapse
|
|
48
|
Qiu L, Du L, Liang Q, Hu H, Tu Z. Synthesis and in vitro evaluation of new TRPV4 ligands and biodistribution study of an 11C-labeled radiotracer in rodents. Bioorg Med Chem Lett 2020; 30:127573. [PMID: 32980513 PMCID: PMC8627648 DOI: 10.1016/j.bmcl.2020.127573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 09/13/2020] [Accepted: 09/18/2020] [Indexed: 11/15/2022]
Abstract
Nine new compounds targeting the transient receptor potential vanilloid-4 (TRPV4) were synthesized and their biological activities toward TRPV4 were determined using freshly isolated mouse skin macrophages through live cell Ca2+ imaging assay. Three compounds 4b, 4c, and 4i exhibited higher percentages of in vitro activation of TRPV4 as 48.1%, 59.3% and 33.5%, which are comparable to 56.4% activation response of the reported TRPV4 agonist GSK1016790A (3). The compound 4i was chosen for 11C-radiosynthesis using its phenol precursor 4g to reacted with [11C]methyl iodide. The radiosynthesis was achieved with good radiochemical yield (16 ± 5%), high chemical and radiochemical purity (>95%), and high molar activity (16-21 GBq/μmol, decay corrected to the end of bombardment, EOB n ≥ 4). Furthermore, the initial ex vivo biodistribution study in rats showed that [11C]4i had higher uptake in kidney, liver and small intestine compared to other tissues with rapid washout.
Collapse
Affiliation(s)
- Lin Qiu
- Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, St. Louis, MO 63110, United States
| | - Lixia Du
- Department of Anesthesiology, Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
| | - Qianwa Liang
- Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, St. Louis, MO 63110, United States
| | - Hongzhen Hu
- Department of Anesthesiology, Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States.
| | - Zhude Tu
- Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, St. Louis, MO 63110, United States.
| |
Collapse
|
|
49
|
Potla R, Hirano-Kobayashi M, Wu H, Chen H, Mammoto A, Matthews BD, Ingber DE. Molecular mapping of transmembrane mechanotransduction through the β1 integrin-CD98hc-TRPV4 axis. J Cell Sci 2020; 133:jcs248823. [PMID: 32989042 PMCID: PMC7657480 DOI: 10.1242/jcs.248823] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 09/17/2020] [Indexed: 01/08/2023] Open
Abstract
One of the most rapid (less than 4 ms) transmembrane cellular mechanotransduction events involves activation of transient receptor potential vanilloid 4 (TRPV4) ion channels by mechanical forces transmitted across cell surface β1 integrin receptors on endothelial cells, and the transmembrane solute carrier family 3 member 2 (herein denoted CD98hc, also known as SLC3A2) protein has been implicated in this response. Here, we show that β1 integrin, CD98hc and TRPV4 all tightly associate and colocalize in focal adhesions where mechanochemical conversion takes place. CD98hc knockdown inhibits TRPV4-mediated calcium influx induced by mechanical forces, but not by chemical activators, thus confirming the mechanospecificity of this signaling response. Molecular analysis reveals that forces applied to β1 integrin must be transmitted from its cytoplasmic C terminus via the CD98hc cytoplasmic tail to the ankyrin repeat domain of TRPV4 in order to produce ultrarapid, force-induced channel activation within the focal adhesion.
Collapse
Affiliation(s)
- Ratnakar Potla
- Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA
| | - Mariko Hirano-Kobayashi
- Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Hao Wu
- Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Hong Chen
- Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Akiko Mammoto
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Benjamin D Matthews
- Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
- Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA
| | - Donald E Ingber
- Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA
- Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, MA 02139, USA
| |
Collapse
|
|
50
|
Achanta S, Jordt SE. Transient receptor potential channels in pulmonary chemical injuries and as countermeasure targets. Ann N Y Acad Sci 2020; 1480:73-103. [PMID: 32892378 PMCID: PMC7933981 DOI: 10.1111/nyas.14472] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 07/22/2020] [Accepted: 07/29/2020] [Indexed: 12/17/2022]
Abstract
The lung is highly sensitive to chemical injuries caused by exposure to threat agents in industrial or transportation accidents, occupational exposures, or deliberate use as weapons of mass destruction (WMD). There are no antidotes for the majority of the chemical threat agents and toxic inhalation hazards despite their use as WMDs for more than a century. Among several putative targets, evidence for transient receptor potential (TRP) ion channels as mediators of injury by various inhalational chemical threat agents is emerging. TRP channels are expressed in the respiratory system and are essential for homeostasis. Among TRP channels, the body of literature supporting essential roles for TRPA1, TRPV1, and TRPV4 in pulmonary chemical injuries is abundant. TRP channels mediate their function through sensory neuronal and nonneuronal pathways. TRP channels play a crucial role in complex pulmonary pathophysiologic events including, but not limited to, increased intracellular calcium levels, signal transduction, recruitment of proinflammatory cells, neurogenic inflammatory pathways, cough reflex, hampered mucus clearance, disruption of the integrity of the epithelia, pulmonary edema, and fibrosis. In this review, we summarize the role of TRP channels in chemical threat agents-induced pulmonary injuries and how these channels may serve as medical countermeasure targets for broader indications.
Collapse
Affiliation(s)
- Satyanarayana Achanta
- Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina
| | - Sven-Eric Jordt
- Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
| |
Collapse
|