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TRP Channels in Physiology and Pathophysiology 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 25 June 2024 | Viewed by 8820

Special Issue Editors


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Guest Editor
Department of Physiology, College of Medicine, University of Arizona, 1501 N Campbell Avenue, Tucson, AZ 85724, USA
Interests: physiology; aqueous humor physiology; lens physiology; pharmacology; signal transduction; cell biology
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Physiology, Faculty of Medical and Health Sciences, New Zealand National Eye Centre, the University of Auckland, Auckland 1142, New Zealand
Interests: ocular tissues; ion channels; transporters; lens; lens transparency; lens cataract
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous successful Special Issue “TRP Channels in Physiology and Pathophysiology”.

As many as thirty TRP channels have been identified with wide distribution and conservation in most organisms, tissues, and cell types. As they are polymodal, TRP channels are activated and regulated by multiple stimuli including chemical ligands (endogenous and exogenous), heat, cold, mechanical stress, osmotic pressure, vibration, pH, and electrical stimulation. TRPs are cation channels which, depending on their differential permeability to Ca2+, can influence numerous downstream signaling pathways that in turn regulate cellular functions that are as diverse as ion transport and homeostasis, fluid secretion, inflammation, pressure and thermoregulation, vision, taste, sense, and smell. Functional TRP channels have been expressed in almost all tissues of the body. Thus, the malfunction, mutation, and over/underexpression of TRPs play roles in many diseases. Based on this emerging body of work on TRP channels, our aim is to publish a Special Issue of IJMS with research and review articles describing current knowledge and data on the sensing, mechanistics, and functional and pathophysiological roles of TRP channels in tissues. We are seeking articles that explore the roles played by TRP channels at molecular, biochemical, physiological, pharmacological, and genetic levels and how they impact the development, normal structure and function, and pathology of all tissues.

Dr. Mohammad Shahidullah
Prof. Dr. Paul James Donaldson
Guest Editors

Manuscript Submission Information

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Keywords

  • transient receptor potential (TRP) channels
  • retina
  • lens
  • lens epithelium
  • ion transport
  • homeostasis
  • ciliary body
  • ciliary epithelium
  • aqueous humor

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Published Papers (10 papers)

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Research

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19 pages, 6608 KiB  
Article
Effect of TRPV4 Antagonist GSK2798745 on Chlorine Gas-Induced Acute Lung Injury in a Swine Model
by Meghan S. Vermillion, Nathan Saari, Mathieu Bray, Andrew M. Nelson, Robert L. Bullard, Karin Rudolph, Andrew P. Gigliotti, Jeffrey Brendler, Jacob Jantzi, Philip J. Kuehl, Jacob D. McDonald, Mark E. Burgert, Waylon Weber, Scott Sucoloski and David J. Behm
Int. J. Mol. Sci. 2024, 25(7), 3949; https://doi.org/10.3390/ijms25073949 - 02 Apr 2024
Viewed by 555
Abstract
As a regulator of alveolo-capillary barrier integrity, Transient Receptor Potential Vanilloid 4 (TRPV4) antagonism represents a promising strategy for reducing pulmonary edema secondary to chemical inhalation. In an experimental model of acute lung injury induced by exposure of anesthetized swine to chlorine gas [...] Read more.
As a regulator of alveolo-capillary barrier integrity, Transient Receptor Potential Vanilloid 4 (TRPV4) antagonism represents a promising strategy for reducing pulmonary edema secondary to chemical inhalation. In an experimental model of acute lung injury induced by exposure of anesthetized swine to chlorine gas by mechanical ventilation, the dose-dependent effects of TRPV4 inhibitor GSK2798745 were evaluated. Pulmonary function and oxygenation were measured hourly; airway responsiveness, wet-to-dry lung weight ratios, airway inflammation, and histopathology were assessed 24 h post-exposure. Exposure to 240 parts per million (ppm) chlorine gas for ≥50 min resulted in acute lung injury characterized by sustained changes in the ratio of partial pressure of oxygen in arterial blood to the fraction of inspiratory oxygen concentration (PaO2/FiO2), oxygenation index, peak inspiratory pressure, dynamic lung compliance, and respiratory system resistance over 24 h. Chlorine exposure also heightened airway response to methacholine and increased wet-to-dry lung weight ratios at 24 h. Following 55-min chlorine gas exposure, GSK2798745 marginally improved PaO2/FiO2, but did not impact lung function, airway responsiveness, wet-to-dry lung weight ratios, airway inflammation, or histopathology. In summary, in this swine model of chlorine gas-induced acute lung injury, GSK2798745 did not demonstrate a clinically relevant improvement of key disease endpoints. Full article
(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)
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15 pages, 2249 KiB  
Article
Pharmacological Activation of TRPC6 Channel Prevents Colitis Progression
by Kazuhiro Nishiyama, Yuri Kato, Akiyuki Nishimura, Xinya Mi, Ryu Nagata, Yasuo Mori, Yasu-Taka Azuma and Motohiro Nishida
Int. J. Mol. Sci. 2024, 25(4), 2401; https://doi.org/10.3390/ijms25042401 - 18 Feb 2024
Cited by 1 | Viewed by 672
Abstract
We recently reported that transient receptor potential canonical (TRPC) 6 channel activity contributes to intracellular Zn2+ homeostasis in the heart. Zn2+ has also been implicated in the regulation of intestinal redox and microbial homeostasis. This study aims to investigate the role [...] Read more.
We recently reported that transient receptor potential canonical (TRPC) 6 channel activity contributes to intracellular Zn2+ homeostasis in the heart. Zn2+ has also been implicated in the regulation of intestinal redox and microbial homeostasis. This study aims to investigate the role of TRPC6-mediated Zn2+ influx in the stress resistance of the intestine. The expression profile of TRPC1-C7 mRNAs in the actively inflamed mucosa from inflammatory bowel disease (IBD) patients was analyzed using the GEO database. Systemic TRPC3 knockout (KO) and TRPC6 KO mice were treated with dextran sulfate sodium (DSS) to induce colitis. The Zn2+ concentration and the mRNA expression levels of oxidative/inflammatory markers in colon tissues were quantitatively analyzed, and gut microbiota profiles were compared. TRPC6 mRNA expression level was increased in IBD patients and DSS-treated mouse colon tissues. DSS-treated TRPC6 KO mice, but not TRPC3 KO mice, showed severe weight loss and increased disease activity index compared with DSS-treated WT mice. The mRNA abundances of antioxidant proteins were basically increased in the TRPC6 KO colon, with changes in gut microbiota profiles. Treatment with TRPC6 activator prevented the DSS-induced colitis progression accompanied by increasing Zn2+ concentration. We suggest that TRPC6-mediated Zn2+ influx activity plays a key role in stress resistance against IBD, providing a new strategy for treating colitis. Full article
(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)
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11 pages, 3128 KiB  
Article
The Lack of TRPA1 Ion Channel Does Not Affect the Chronic Stress-Induced Activation of the Locus Ceruleus
by Milica Milicic, Balázs Gaszner, Gergely Berta, Erika Pintér and Viktória Kormos
Int. J. Mol. Sci. 2024, 25(3), 1765; https://doi.org/10.3390/ijms25031765 - 01 Feb 2024
Viewed by 566
Abstract
We have previously proven the involvement of transient receptor potential ankyrin 1 (TRPA1) in stress adaptation. A lack of TRPA1 affects both urocortin 1 (member of the corticotropin-releasing hormone (CRH) family) content of the Edinger–Westphal nucleus. The noradrenergic locus ceruleus (LC) is also [...] Read more.
We have previously proven the involvement of transient receptor potential ankyrin 1 (TRPA1) in stress adaptation. A lack of TRPA1 affects both urocortin 1 (member of the corticotropin-releasing hormone (CRH) family) content of the Edinger–Westphal nucleus. The noradrenergic locus ceruleus (LC) is also an important player in mood control. We aimed at investigating whether the TRPA1 is expressed in the LC, and to test if the response to chronic variable mild stress (CVMS) is affected by a lack of TRPA1. The TRPA1 expression was examined via RNAscope in situ hybridization. We investigated TRPA1 knockout and wildtype mice using the CVMS model of depression. Tyrosine hydroxylase (TH) and FOSB double immunofluorescence were used to test the functional neuromorphological changes in the LC. No TRPA1 expression was detected in the LC. The TH content was not affected by CVMS exposure. The CVMS-induced FOSB immunosignal did not co-localize with the TH neurons. TRPA1 is not expressed in the LC. A lack of functional TRPA1 receptor neither directly nor indirectly affects the TH content of LC neurons under CVMS. Full article
(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)
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17 pages, 3089 KiB  
Article
Joint CB1 and NGF Receptor Activation Suppresses TRPM8 Activation in Etoposide-Resistant Retinoblastoma Cells
by Szymon Ludwiczak, Jacqueline Reinhard, Peter S. Reinach, Aruna Li, Jakub Oronowicz, Aisha Yousf, Vinodh Kakkassery and Stefan Mergler
Int. J. Mol. Sci. 2024, 25(3), 1733; https://doi.org/10.3390/ijms25031733 - 31 Jan 2024
Viewed by 768
Abstract
In childhood, retinoblastoma (RB) is the most common primary tumor in the eye. Long term therapeutic management with etoposide of this life-threatening condition may have diminishing effectiveness since RB cells can develop cytostatic resistance to this drug. To determine whether changes in receptor-mediated [...] Read more.
In childhood, retinoblastoma (RB) is the most common primary tumor in the eye. Long term therapeutic management with etoposide of this life-threatening condition may have diminishing effectiveness since RB cells can develop cytostatic resistance to this drug. To determine whether changes in receptor-mediated control of Ca2+ signaling are associated with resistance development, fluorescence calcium imaging, semi-quantitative RT-qPCR analyses, and trypan blue dye exclusion staining patterns are compared in WERI-ETOR (etoposide-insensitive) and WERI-Rb1 (etoposide-sensitive) cells. The cannabinoid receptor agonist 1 (CNR1) WIN55,212-2 (40 µM), or the transient receptor potential melastatin 8 (TRPM8) agonist icilin (40 µM) elicit similar large Ca2+ transients in both cell line types. On the other hand, NGF (100 ng/mL) induces larger rises in WERI-ETOR cells than in WERI-Rb1 cells, and its lethality is larger in WERI-Rb1 cells than in WERI-ETOR cells. NGF and WIN55,212-2 induced additive Ca2+ transients in both cell types. However, following pretreatment with both NGF and WIN55,212-2, TRPM8 gene expression declines and icilin-induced Ca2+ transients are completely blocked only in WERI-ETOR cells. Furthermore, CNR1 gene expression levels are larger in WERI-ETOR cells than those in WERI-Rb1 cells. Therefore, the development of etoposide insensitivity may be associated with rises in CNR1 gene expression, which in turn suppress TRPM8 gene expression through crosstalk. Full article
(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)
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27 pages, 4319 KiB  
Article
Bidirectional Allosteric Coupling between PIP2 Binding and the Pore of the Oncochannel TRPV6
by Christina Humer, Tamara Radiskovic, Kata Horváti, Sonja Lindinger, Klaus Groschner, Christoph Romanin and Carmen Höglinger
Int. J. Mol. Sci. 2024, 25(1), 618; https://doi.org/10.3390/ijms25010618 - 03 Jan 2024
Viewed by 920
Abstract
The epithelial ion channel TRPV6 plays a pivotal role in calcium homeostasis. Channel function is intricately regulated at different stages, involving the lipid phosphatidylinositol-4,5-bisphosphate (PIP2). Given that dysregulation of TRPV6 is associated with various diseases, including different types of cancer, there [...] Read more.
The epithelial ion channel TRPV6 plays a pivotal role in calcium homeostasis. Channel function is intricately regulated at different stages, involving the lipid phosphatidylinositol-4,5-bisphosphate (PIP2). Given that dysregulation of TRPV6 is associated with various diseases, including different types of cancer, there is a compelling need for its pharmacological targeting. Structural studies provide insights on how TRPV6 is affected by different inhibitors, with some binding to sites else occupied by lipids. These include the small molecule cis-22a, which, however, also binds to and thereby blocks the pore. By combining calcium imaging, electrophysiology and optogenetics, we identified residues within the pore and the lipid binding site that are relevant for regulation by cis-22a and PIP2 in a bidirectional manner. Yet, mutation of the cytosolic pore exit reduced inhibition by cis-22a but preserved sensitivity to PIP2 depletion. Our data underscore allosteric communication between the lipid binding site and the pore and vice versa for most sites along the pore. Full article
(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)
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29 pages, 14818 KiB  
Article
Cold-Temperature Coding with Bursting and Spiking Based on TRP Channel Dynamics in Drosophila Larva Sensory Neurons
by Natalia Maksymchuk, Akira Sakurai, Daniel N. Cox and Gennady S. Cymbalyuk
Int. J. Mol. Sci. 2023, 24(19), 14638; https://doi.org/10.3390/ijms241914638 - 27 Sep 2023
Viewed by 949
Abstract
Temperature sensation involves thermosensitive TRP (thermoTRP) and non-TRP channels. Drosophila larval Class III (CIII) neurons serve as the primary cold nociceptors and express a suite of thermoTRP channels implicated in noxious cold sensation. How CIII neurons code temperature remains unclear. We combined computational [...] Read more.
Temperature sensation involves thermosensitive TRP (thermoTRP) and non-TRP channels. Drosophila larval Class III (CIII) neurons serve as the primary cold nociceptors and express a suite of thermoTRP channels implicated in noxious cold sensation. How CIII neurons code temperature remains unclear. We combined computational and electrophysiological methods to address this question. In electrophysiological experiments, we identified two basic cold-evoked patterns of CIII neurons: bursting and spiking. In response to a fast temperature drop to noxious cold, CIII neurons distinctly mark different phases of the stimulus. Bursts frequently occurred along with the fast temperature drop, forming a peak in the spiking rate and likely coding the high rate of the temperature change. Single spikes dominated at a steady temperature and exhibited frequency adaptation following the peak. When temperature decreased slowly to the same value, mainly spiking activity was observed, with bursts occurring sporadically throughout the stimulation. The spike and the burst frequencies positively correlated with the rate of the temperature drop. Using a computational model, we explain the distinction in the occurrence of the two CIII cold-evoked patterns bursting and spiking using the dynamics of a thermoTRP current. A two-parameter activity map (Temperature, constant TRP current conductance) marks parameters that support silent, spiking, and bursting regimes. Projecting on the map the instantaneous TRP conductance, governed by activation and inactivation processes, reflects temperature coding responses as a path across silent, spiking, or bursting domains on the map. The map sheds light on how various parameter sets for TRP kinetics represent various types of cold-evoked responses. Together, our results indicate that bursting detects the high rate of temperature change, whereas tonic spiking could reflect both the rate of change and magnitude of steady cold temperature. Full article
(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)
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9 pages, 1956 KiB  
Article
Canonical Transient Receptor Potential Channel 3 Contributes to Cerebral Blood Flow Changes Associated with Cortical Spreading Depression in Mice
by Fang Zheng
Int. J. Mol. Sci. 2023, 24(16), 12611; https://doi.org/10.3390/ijms241612611 - 09 Aug 2023
Viewed by 815
Abstract
Cortical spreading depression is a pathophysiological event shared in migraines, strokes, traumatic brain injuries, and epilepsy. It is associated with complex hemodynamic responses, which, in turn, contribute to neurological problems. In this study, we investigated the role of canonical transient receptor potential channel [...] Read more.
Cortical spreading depression is a pathophysiological event shared in migraines, strokes, traumatic brain injuries, and epilepsy. It is associated with complex hemodynamic responses, which, in turn, contribute to neurological problems. In this study, we investigated the role of canonical transient receptor potential channel 3 (TRPC3) in the hemodynamic responses elicited by cortical spreading depression. Cerebral blood flow was monitored using laser speckle contrast imaging, and cortical spreading depression was triggered using three well-established experimental approaches in mice. A comparison of TRPC3 knockout mice to controls revealed that the genetic ablation of TRPC3 expression significantly altered the hemodynamic responses elicited using cortical spreading depression and promoted hyperemia consistently. Our results indicate that TRPC3 contributes to hemodynamic responses associated with cortical spreading depression and could be a novel therapeutic target for a host of neurological disorders. Full article
(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)
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Review

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14 pages, 1263 KiB  
Review
Impact of TRP Channels on Extracellular Matrix Remodeling: Focus on TRPV4 and Collagen
by Qin Wang, Chenfan Ji, Patricio Smith and Christopher A. McCulloch
Int. J. Mol. Sci. 2024, 25(7), 3566; https://doi.org/10.3390/ijms25073566 - 22 Mar 2024
Viewed by 540
Abstract
Disturbed remodeling of the extracellular matrix (ECM) is frequently observed in several high-prevalence pathologies that include fibrotic diseases of organs such as the heart, lung, periodontium, liver, and the stiffening of the ECM surrounding invasive cancers. In many of these lesions, matrix remodeling [...] Read more.
Disturbed remodeling of the extracellular matrix (ECM) is frequently observed in several high-prevalence pathologies that include fibrotic diseases of organs such as the heart, lung, periodontium, liver, and the stiffening of the ECM surrounding invasive cancers. In many of these lesions, matrix remodeling mediated by fibroblasts is dysregulated, in part by alterations to the regulatory and effector systems that synthesize and degrade collagen, and by alterations to the functions of the integrin-based adhesions that normally mediate mechanical remodeling of collagen fibrils. Cell-matrix adhesions containing collagen-binding integrins are enriched with regulatory and effector systems that initiate localized remodeling of pericellular collagen fibrils to maintain ECM homeostasis. A large cadre of regulatory molecules is enriched in cell-matrix adhesions that affect ECM remodeling through synthesis, degradation, and contraction of collagen fibrils. One of these regulatory molecules is Transient Receptor Potential Vanilloid-type 4 (TRPV4), a mechanically sensitive, Ca2+-permeable plasma membrane channel that regulates collagen remodeling. The gating of Ca2+ across the plasma membrane by TRPV4 and the consequent generation of intracellular Ca2+ signals affect several processes that determine the structural and mechanical properties of collagen-rich ECM. These processes include the synthesis of new collagen fibrils, tractional remodeling by contractile forces, and collagenolysis. While the specific mechanisms by which TRPV4 contributes to matrix remodeling are not well-defined, it is known that TRPV4 is activated by mechanical forces transmitted through collagen adhesion receptors. Here, we consider how TRPV4 expression and function contribute to physiological and pathological collagen remodeling and are associated with collagen adhesions. Over the long-term, an improved understanding of how TRPV4 regulates collagen remodeling could pave the way for new approaches to manage fibrotic lesions. Full article
(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)
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30 pages, 23872 KiB  
Review
Role of TRP Channels in Metabolism-Related Diseases
by Fengming Wu, Siyuan Bu and Hongmei Wang
Int. J. Mol. Sci. 2024, 25(2), 692; https://doi.org/10.3390/ijms25020692 - 05 Jan 2024
Cited by 1 | Viewed by 1103
Abstract
Metabolic syndrome (MetS), with its high prevalence and significant impact on cardiovascular disease, poses a substantial threat to human health. The early identification of pathological abnormalities related to MetS and prevention of the risk of associated diseases is of paramount importance. Transient Receptor [...] Read more.
Metabolic syndrome (MetS), with its high prevalence and significant impact on cardiovascular disease, poses a substantial threat to human health. The early identification of pathological abnormalities related to MetS and prevention of the risk of associated diseases is of paramount importance. Transient Receptor Potential (TRP) channels, a type of nonselective cation channel, are expressed in a variety of tissues and have been implicated in the onset and progression of numerous metabolism-related diseases. This study aims to review and discuss the expression and function of TRP channels in metabolism-related tissues and blood vessels, and to elucidate the interactions and mechanisms between TRP channels and metabolism-related diseases. A comprehensive literature search was conducted using keywords such as TRP channels, metabolic syndrome, pancreas, liver, oxidative stress, diabetes, hypertension, and atherosclerosis across various academic databases including PubMed, Google Scholar, Elsevier, Web of Science, and CNKI. Our review of the current research suggests that TRP channels may be involved in the development of metabolism-related diseases by regulating insulin secretion and release, lipid metabolism, vascular functional activity, oxidative stress, and inflammatory response. TRP channels, as nonselective cation channels, play pivotal roles in sensing various intra- and extracellular stimuli and regulating ion homeostasis by osmosis. They present potential new targets for the diagnosis or treatment of metabolism-related diseases. Full article
(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)
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21 pages, 1319 KiB  
Review
Interaction of Calmodulin with TRPM: An Initiator of Channel Modulation
by Kristyna Vydra Bousova, Monika Zouharova, Katerina Jiraskova and Veronika Vetyskova
Int. J. Mol. Sci. 2023, 24(20), 15162; https://doi.org/10.3390/ijms242015162 - 13 Oct 2023
Cited by 1 | Viewed by 1129
Abstract
Transient receptor potential melastatin (TRPM) channels, a subfamily of the TRP superfamily, constitute a diverse group of ion channels involved in mediating crucial cellular processes like calcium homeostasis. These channels exhibit complex regulation, and one of the key regulatory mechanisms involves their interaction [...] Read more.
Transient receptor potential melastatin (TRPM) channels, a subfamily of the TRP superfamily, constitute a diverse group of ion channels involved in mediating crucial cellular processes like calcium homeostasis. These channels exhibit complex regulation, and one of the key regulatory mechanisms involves their interaction with calmodulin (CaM), a cytosol ubiquitous calcium-binding protein. The association between TRPM channels and CaM relies on the presence of specific CaM-binding domains in the channel structure. Upon CaM binding, the channel undergoes direct and/or allosteric structural changes and triggers down- or up-stream signaling pathways. According to current knowledge, ion channel members TRPM2, TRPM3, TRPM4, and TRPM6 are directly modulated by CaM, resulting in their activation or inhibition. This review specifically focuses on the interplay between TRPM channels and CaM and summarizes the current known effects of CaM interactions and modulations on TRPM channels in cellular physiology. Full article
(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)
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