Angiotensin-II Drives Human Satellite Cells Toward Hypertrophy and Myofibroblast Trans-Differentiation by Two Independent Pathways

Skeletal muscle regeneration is ensured by satellite cells (SC), which upon activation undergo self-renewal and myogenesis. The correct sequence of healing events may be offset by inflammatory and/or fibrotic factors able to promote fibrosis and consequent muscle wasting. Angiotensin-II (Ang) is an effector peptide of the renin angiotensin system (RAS), of which the direct role in human SCs (hSCs) is still controversial. Based on the hypertrophic and fibrogenic effects of Ang via transient receptor potential canonical (TRPC) channels in cardiac and renal tissues, we hypothesized a similar axis in hSCs. Toward this aim, we demonstrated that hSCs respond to acute Ang stimulation, dose-dependently enhancing p-mTOR, p-AKT, p-ERK1/2 and p-P38. Additionally, sub-acute Ang conditioning increased cell size and promoted trans-differentiation into myofibroblasts. To provide a mechanistic hypothesis on TRPC channel involvement in the processes, we proved that TRPC channels mediate a basal calcium entry into hSCs that is stimulated by acute Ang and strongly amplified by sub-chronic Ang conditioning. Altogether, these findings demonstrate that Ang induces a fate shift of hSCs into myofibroblasts and provide a basis to support a benefit of RAS and TRPC channel blockade to oppose muscle fibrosis.

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Neuropeptide RFRP inhibits the pacemaker activity of terminal nerve GnRH neurons

Journal of Neurophysiology ◽

10.1152/jn.00712.2012 ◽

2013 ◽

Vol 109 (9) ◽

pp. 2354-2363 ◽

Cited By ~ 11

Author(s):

Chie Umatani ◽

Hideki Abe ◽

Yoshitaka Oka

Keyword(s):

Transient Receptor Potential ◽

Reversal Potential ◽

Receptor Potential ◽

Pacemaker Activity ◽

Trpc Channels ◽

Induced Current ◽

Reproductive Behaviors ◽

Trpc Channel ◽

Terminal Nerve ◽

Gnrh Neurons

The terminal nerve gonadotropin-releasing hormone (TN-GnRH) neurons show spontaneous pacemaker activity whose firing frequency is suggested to regulate the release of GnRH peptides and control motivation for reproductive behaviors. Previous studies of the electrophysiological properties of TN-GnRH neurons reported excitatory modulation of pacemaker activity by auto/paracrine and synaptic modulations, but inhibition of pacemaker activity has not been reported to date. Our recent study suggests that neuropeptide FF, a type of Arg-Phe-amide (RFamide) peptide expressed in TN-GnRH neurons themselves, inhibits the pacemaker activity of TN-GnRH neurons in an auto- and paracrine manner. In the present study, we examined whether RFamide-related peptides (RFRPs), which are produced in the hypothalamus, modulate the pacemaker activity of TN-GnRH neurons as candidate inhibitory synaptic modulators. Bath application of RFRP2, among the three teleost RFRPs, decreased the frequency of firing of TN-GnRH neurons. This inhibition was diminished by RF9, a potent antagonist of GPR147/74, which are candidate RFRP receptors. RFRP2 changed the conductances for Na+ and K+. The reversal potential for RFRP2-induced current was altered by inhibitors of the transient receptor potential canonical (TRPC) channel (La3+ and 2-aminoethoxydiphenyl borate) and by a less selective blocker of voltage-independent K+ channels (Ba2+). By comparing the current-voltage relationship in artificial cerebrospinal fluid with that under each drug, the RFRP2-induced current was suggested to consist of TRPC channel-like current and voltage-independent K+ current. Therefore, synaptic release of RFRP2 from hypothalamic neurons is suggested to inhibit the pacemaker activity of TN-GnRH neurons by closing TRPC channels and opening voltage-independent K+ channels. This novel pathway may negatively regulate reproductive behaviors.

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Pharmacology of TRPC Channels and Its Potential in Cardiovascular and Metabolic Medicine

The Annual Review of Pharmacology and Toxicology ◽

10.1146/annurev-pharmtox-030121-122314 ◽

2021 ◽

Vol 62 (1) ◽

Author(s):

Robin S. Bon ◽

David J. Wright ◽

David J. Beech ◽

Piruthivi Sukumar

Keyword(s):

Transient Receptor Potential ◽

Receptor Potential ◽

Annual Review ◽

Publication Date ◽

Trpc Channels ◽

Trpc Channel ◽

Channel Inhibition ◽

Transient Receptor ◽

Physical And Chemical ◽

Trpc Proteins

Transient receptor potential canonical (TRPC) proteins assemble to form homo- or heterotetrameric, nonselective cation channels permeable to K+, Na+, and Ca2+. TRPC channels are thought to act as complex integrators of physical and chemical environmental stimuli. Although the understanding of essential physiological roles of TRPC channels is incomplete, their implication in various pathological mechanisms and conditions of the nervous system, kidneys, and cardiovascular system in combination with the lack of major adverse effects of TRPC knockout or TRPC channel inhibition is driving the search of TRPC channel modulators as potential therapeutics. Here, we review the most promising small-molecule TRPC channel modulators, the understanding of their mode of action, and their potential in the study and treatment of cardiovascular and metabolic disease. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Emerging Roles of Diacylglycerol-Sensitive TRPC4/5 Channels

Cells ◽

10.3390/cells7110218 ◽

2018 ◽

Vol 7 (11) ◽

pp. 218 ◽

Cited By ~ 9

Author(s):

Michael Mederos y Schnitzler ◽

Thomas Gudermann ◽

Ursula Storch

Keyword(s):

Transient Receptor Potential ◽

Receptor Potential ◽

Receptor Activation ◽

Activation Mechanism ◽

Regulatory Function ◽

Cation Channels ◽

Trpc Channels ◽

Trpc Channel ◽

Transient Receptor ◽

Trpc5 Channels

Transient receptor potential classical or canonical 4 (TRPC4) and TRPC5 channels are members of the classical or canonical transient receptor potential (TRPC) channel family of non-selective cation channels. TRPC4 and TRPC5 channels are widely accepted as receptor-operated cation channels that are activated in a phospholipase C-dependent manner, following the Gq/11 protein-coupled receptor activation. However, their precise activation mechanism has remained largely elusive for a long time, as the TRPC4 and TRPC5 channels were considered as being insensitive to the second messenger diacylglycerol (DAG) in contrast to the other TRPC channels. Recent findings indicate that the C-terminal interactions with the scaffolding proteins Na+/H+ exchanger regulatory factor 1 and 2 (NHERF1 and NHERF2) dynamically regulate the DAG sensitivity of the TRPC4 and TRPC5 channels. Interestingly, the C-terminal NHERF binding suppresses, while the dissociation of NHERF enables, the DAG sensitivity of the TRPC4 and TRPC5 channels. This leads to the assumption that all of the TRPC channels are DAG sensitive. The identification of the regulatory function of the NHERF proteins in the TRPC4/5-NHERF protein complex offers a new starting point to get deeper insights into the molecular basis of TRPC channel activation. Future studies will have to unravel the physiological and pathophysiological functions of this multi-protein channel complex.

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Transient Receptor Potential Canonical Channels in Health and Disease: A 2020 Update

Cells ◽

10.3390/cells10030496 ◽

2021 ◽

Vol 10 (3) ◽

pp. 496

Author(s):

Priya R. Kirtley ◽

Gagandeep S. Sooch ◽

Fletcher A. White ◽

Alexander G. Obukhov

Keyword(s):

Transient Receptor Potential ◽

Receptor Potential ◽

Trpc Channels ◽

Special Issue ◽

25Th Anniversary ◽

Trpc Channel ◽

Transient Receptor Potential Canonical ◽

Health And Disease ◽

Transient Receptor

This 2020 Special Issue “TRPC channels” of Cells was dedicated to commemorating the 25th anniversary of discovery of the Transient Receptor Potential Canonical (TRPC) channel subfamily [...]

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TRPC1/5-CaV3 Complex Mediates Leptin-Induced Excitability in Hypothalamic Neurons

Frontiers in Neuroscience ◽

10.3389/fnins.2021.679078 ◽

2021 ◽

Vol 15 ◽

Author(s):

Paula P. Perissinotti ◽

Elizabeth Martínez-Hernández ◽

Erika S. Piedras-Rentería

Keyword(s):

Transient Receptor Potential ◽

Receptor Potential ◽

Membrane Depolarization ◽

Resting Membrane Potential ◽

Macromolecular Complex ◽

Trpc Channels ◽

Hypothalamic Neurons ◽

Trpc Channel ◽

Neuron Excitability

Leptin regulates hypothalamic POMC+ (pro-opiomelanocortin) neurons by inducing TRPC (Transient Receptor Potential Cation) channel-mediate membrane depolarization. The role of TRPC channels in POMC neuron excitability is clearly established; however, it remains unknown whether their activity alone is sufficient to trigger excitability. Here we show that the right-shift voltage induced by the leptin-induced TRPC channel-mediated depolarization of the resting membrane potential brings T-type channels into the active window current range, resulting in an increase of the steady state T-type calcium current from 40 to 70% resulting in increased intrinsic excitability of POMC neurons. We assessed the role and timing of T-type channels on excitability and leptin-induced depolarization in vitro in cultured mouse POMC neurons. The involvement of TRPC channels in the leptin-induced excitability of POMC neurons was corroborated by using the TRPC channel inhibitor 2APB, which precluded the effect of leptin. We demonstrate T-type currents are indispensable for both processes, as treatment with NNC-55-0396 prevented the membrane depolarization and rheobase changes induced by leptin. Furthermore, co-immunoprecipitation experiments suggest that TRPC1/5 channels and CaV3.1 and CaV3.2 channels co-exist in complex. The functional relevance of this complex was corroborated using intracellular Ca2+ chelators; intracellular BAPTA (but not EGTA) application was sufficient to preclude POMC neuron excitability. However, leptin-induced depolarization still occurred in the presence of either BAPTA or EGTA suggesting that the calcium entry necessary to self-activate the TRPC1/5 complex is not blocked by the presence of BAPTA in hypothalamic neurons. Our study establishes T-type channels as integral part of the signaling cascade induced by leptin, modulating POMC neuron excitability. Leptin activation of TRPC channels existing in a macromolecular complex with T-type channels recruits the latter by locally induced membrane depolarization, further depolarizing POMC neurons, triggering action potentials and excitability.

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The Na+/Ca2+ Exchanger Inhibitor, KB-R7943, Blocks a Nonselective Cation Channel Implicated in Chemosensory Transduction

Journal of Neurophysiology ◽

10.1152/jn.90903.2008 ◽

2009 ◽

Vol 101 (3) ◽

pp. 1151-1159 ◽

Cited By ~ 12

Author(s):

A. Pezier ◽

Y. V. Bobkov ◽

B. W. Ache

Keyword(s):

Transient Receptor Potential ◽

Single Channel ◽

Receptor Potential ◽

Trpc Channels ◽

Dependent Manner ◽

Open Probability ◽

Olfactory Transduction ◽

Voltage Dependent ◽

Chemosensory Transduction ◽

Transient Receptor

The mechanism(s) of olfactory transduction in invertebrates remains to be fully understood. In lobster olfactory receptor neurons (ORNs), a nonselective sodium-gated cation (SGC) channel, a presumptive transient receptor potential (TRP)C channel homolog, plays a crucial role in olfactory transduction, at least in part by amplifying the primary transduction current. To better determine the functional role of the channel, it is important to selectively block the channel independently of other elements of the transduction cascade, causing us to search for specific pharmacological blockers of the SGC channel. Given evidence that the Na+/Ca2+ exchange inhibitor, KB-R7943, blocks mammalian TRPC channels, we studied this probe as a potential blocker of the lobster SGC channel. KB-R7943 reversibly blocked the SGC current in both inside- and outside-out patch recordings in a dose- and voltage-dependent manner. KB-R7943 decreased the channel open probability without changing single channel amplitude. KB-R7943 also reversibly and in a dose-dependent manner inhibited both the odorant-evoked discharge of lobster ORNs and the odorant-evoked whole cell current. Our findings strongly imply that KB-R7943 potently blocks the lobster SGC channel and likely does so directly and not through its ability to block the Na+/Ca2+ exchanger.

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Mineralocorticoid receptor antagonism improves parenchymal arteriole dilation via a TRPV4-dependent mechanism and prevents cognitive dysfunction in hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00207.2018 ◽

2018 ◽

Vol 315 (5) ◽

pp. H1304-H1315 ◽

Cited By ~ 10

Author(s):

Janice M. Diaz-Otero ◽

Ting-Chieh Yen ◽

Courtney Fisher ◽

Daniel Bota ◽

William F. Jackson ◽

...

Keyword(s):

Cognitive Function ◽

Angiotensin Ii ◽

Mineralocorticoid Receptor ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Receptor Activation ◽

Myogenic Tone ◽

Transient Receptor Potential Vanilloid ◽

Cerebrovascular Function ◽

Transient Receptor

Hypertension and mineralocorticoid receptor activation cause cerebral parenchymal arteriole remodeling; this can limit cerebral perfusion and contribute to cognitive dysfunction. We used a mouse model of angiotensin II-induced hypertension to test the hypothesis that mineralocorticoid receptor activation impairs both transient receptor potential vanilloid (TRPV)4-mediated dilation of cerebral parenchymal arterioles and cognitive function. Mice (16−18 wk old, male, C57Bl/6) were treated with angiotensin II (800 ng·kg−1·min−1) with or without the mineralocorticoid receptor antagonist eplerenone (100 mg·kg−1·day−1) for 4 wk; sham mice served as controls. Data are presented as means ± SE; n = 5–14 mice/group. Eplerenone prevented the increased parenchymal arteriole myogenic tone and impaired carbachol-induced (10−9–10−5 mol/l) dilation observed during hypertension. The carbachol-induced dilation was endothelium-derived hyperpolarization mediated because it could not be blocked by N-nitro-l-arginine methyl ester (10−5 mol/l) and indomethacin (10−4 mol/l). We used GSK2193874 (10−7 mol/l) to confirm that in all groups this dilation was dependent on TRPV4 activation. Dilation in response to the TRPV4 agonist GSK1016790A (10−9–10−5 mol/l) was also reduced in hypertensive mice, and this defect was corrected by eplerenone. In hypertensive and eplerenone-treated animals, TRPV4 inhibition reduced myogenic tone, an effect that was not observed in arterioles from control animals. Eplerenone treatment also improved cognitive function and reduced microglia density in hypertensive mice. These data suggest that the mineralocorticoid receptor is a potential therapeutic target to improve cerebrovascular function and cognition during hypertension. NEW & NOTEWORTHY Vascular dementia is a growing public health issue that lacks effective treatments. Transient receptor potential vanilloid (TRPV)4 channels are important regulators of parenchymal arteriole dilation, and they modulate myogenic tone. The data presented here suggest that TRPV4 channel expression is regulated by the mineralocorticoid receptor (MR). MR blockade also improves cognitive function during hypertension. MR blockade might be a potential therapeutic approach to improve cerebrovascular function and cognition in patients with hypertension.

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Regulation of Transient Receptor Potential Canonical 4 Activity by Phospholipase C-δ1

10.21203/rs.3.rs-107953/v1 ◽

2020 ◽

Author(s):

Juyeon Ko ◽

Jongyun Myeong ◽

Misun Kwak ◽

Insuk So

Keyword(s):

Phospholipase C ◽

Transient Receptor Potential ◽

Resonance Energy Transfer ◽

Resonance Energy ◽

Receptor Potential ◽

Regulation Mechanism ◽

Trpc Channels ◽

Transient Receptor Potential Canonical ◽

Cell Current ◽

Transient Receptor

Abstract Transient receptor potential canonical (TRPC) channels are non-selective calcium-permeable cation channels. It is suggested that TRPC4β and TRPC5 channels are regulated by phospholipase C (PLC) signaling, and are especially maintained by phosphatidylinositol 4,5-bisphosphate (PIP2). The PLCδ subtype is the most Ca2+-sensitive form among the isozymes which cleaves phospholipids to respond to the calcium rise. In this study, we investigated the regulation mechanism of TRPC channel by Ca2+, PLCδ1 and PIP2 signaling cascades. The interaction between TRPC4β and PLCδ1 was identified through the Fӧster resonance energy transfer (FRET) and co-immunoprecipitation (Co-IP). With the electrophysiological experiments, we found that TRPC4β-bound PLCδ1 reduces the overall whole-cell current of channel. The Ca2+-via opened channel promotes the activation of PLCδ1, which subsequently decreases PIP2 level. By comparison TRPC4β activity with or without PLCδ1 using differently [Ca2+]i buffered solution, we demonstrated that PLCδ1 functions in normal condition with physiological calcium range. The negative regulation effect of PLCδ1 on TRPC4β helps to elucidate the roles of each PIP2 binding residues whether they are concerned in channel maintenance or inhibition of channel activity.

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Canonical Transient Receptor Potential (TRPC) Channels in Nociception and Pathological Pain

Neural Plasticity ◽

10.1155/2020/3764193 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Zhi-Chuan Sun ◽

Sui-Bin Ma ◽

Wen-Guang Chu ◽

Dong Jia ◽

Ceng Luo

Keyword(s):

Chronic Pain ◽

Molecular Mechanisms ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Trpc Channels ◽

Canonical Transient Receptor Potential ◽

Abnormal Increase ◽

Pathological Pain ◽

Transient Receptor ◽

Underlying Mechanisms

Chronic pathological pain is one of the most intractable clinical problems faced by clinicians and can be devastating for patients. Despite much progress we have made in understanding chronic pain in the last decades, its underlying mechanisms remain elusive. It is assumed that abnormal increase of calcium levels in the cells is a key determinant in the transition from acute to chronic pain. Exploring molecular players mediating Ca2+ entry into cells and molecular mechanisms underlying activity-dependent changes in Ca2+ signaling in the somatosensory pain pathway is therefore helpful towards understanding the development of chronic, pathological pain. Canonical transient receptor potential (TRPC) channels form a subfamily of nonselective cation channels, which permit the permeability of Ca2+ and Na+ into the cells. Initiation of Ca2+ entry pathways by these channels triggers the development of many physiological and pathological functions. In this review, we will focus on the functional implication of TRPC channels in nociception with the elucidation of their role in the detection of external stimuli and nociceptive hypersensitivity.

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Structure–Function Relationship and Physiological Roles of Transient Receptor Potential Canonical (TRPC) 4 and 5 Channels

Cells ◽

10.3390/cells9010073 ◽

2019 ◽

Vol 9 (1) ◽

pp. 73

Author(s):

Jinsung Kim ◽

Juyeon Ko ◽

Chansik Hong ◽

Insuk So

Keyword(s):

Ion Channels ◽

Structure Function ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Trpc Channels ◽

Transient Receptor Potential Canonical ◽

Structure Function Relationship ◽

Transient Receptor ◽

Function Relationship ◽

Relationship Of

The study of the structure–function relationship of ion channels has been one of the most challenging goals in contemporary physiology. Revelation of the three-dimensional (3D) structure of ion channels has facilitated our understanding of many of the submolecular mechanisms inside ion channels, such as selective permeability, voltage dependency, agonist binding, and inter-subunit multimerization. Identifying the structure–function relationship of the ion channels is clinically important as well since only such knowledge can imbue potential therapeutics with practical possibilities. In a sense, recent advances in the understanding of the structure–relationship of transient receptor potential canonical (TRPC) channels look promising since human TRPC channels are calcium-permeable, non-selective cation channels expressed in many tissues such as the gastrointestinal (GI) tract, kidney, heart, vasculature, and brain. TRPC channels are known to regulate GI contractility and motility, pulmonary hypertension, right ventricular hypertrophy, podocyte injury, seizure, fear, anxiety-like behavior, and many others. In this article, we tried to elaborate recent findings of Cryo-EM (cryogenic-electron microscopy) based structural information of TRPC 4 and 5 channels and domain-specific functions of the channel, such as G-protein mediated activation mechanism, extracellular modification of the channel, homo/hetero-tetramerization, and pharmacological gating mechanisms.

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