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

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.

scholarly journals TRPC5-CaV3 complex mediates Leptin-induced excitability in hypothalamic neurons

2020 ◽  
Author(s):  
Paula P. Perissinotti ◽  
Elizabeth Martínez-Hernández ◽  
Erika S. Piedras-Rentería
Keyword(s):  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Receptor Potential ◽  
Membrane Depolarization ◽  
Macromolecular Complex ◽  
Trpc Channels ◽  
Neuron Excitability ◽  
Intracellular Ca ◽  
Transient Receptor

ABSTRACTLeptin regulates hypothalamic POMC+ (pro-opiomelanocortin) neurons by inducing TRPC (Transient Receptor Potential Cation) channel-mediate membrane depolarization. Here we assessed the role of T-type channels on POMC neuron excitability and leptin-induced depolarization in vitro. 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 in cultured mouse POMC neurons. Furthermore, we demonstrate TRPC1/C5 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 by preventing leptin-induced calcium influx through TRPC channels and T-type channel function.We conclude T-type channels are integral in 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.

scholarly journals Major contribution of the 3/6/7 class of TRPC channels to myocardial ischemia/reperfusion and cellular hypoxia/reoxygenation injuries

2017 ◽  
Vol 114 (23) ◽  
pp. E4582-E4591 ◽  
Author(s):  
Xiju He ◽  
Shoutian Li ◽  
Benju Liu ◽  
Sebastian Susperreguy ◽  
Karina Formoso ◽  
...  
Keyword(s):  
Calcium Release ◽  
Transient Receptor Potential ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Receptor Potential ◽  
Permeability Transition ◽  
Transient Receptor Potential Channels ◽  
Trpc Channels ◽  
Potential Channels

The injury phase after myocardial infarcts occurs during reperfusion and is a consequence of calcium release from internal stores combined with calcium entry, leading to cell death by apoptopic and necrotic processes. The mechanism(s) by which calcium enters cells has(ve) not been identified. Here, we identify canonical transient receptor potential channels (TRPC) 3 and 6 as the cation channels through which most of the damaging calcium enters cells to trigger their death, and we describe mechanisms activated during the injury phase. Working in vitro with H9c2 cardiomyoblasts subjected to 9-h hypoxia followed by 6-h reoxygenation (H/R), and analyzing changes occurring in areas-at-risk (AARs) of murine hearts subjected to a 30-min ischemia followed by 24-h reperfusion (I/R) protocol, we found: (i) that blocking TRPC with SKF96365 significantly ameliorated damage induced by H/R, including development of the mitochondrial permeability transition and proapoptotic changes in Bcl2/BAX ratios; and (ii) that AAR tissues had increased TUNEL+ cells, augmented Bcl2/BAX ratios, and increased p(S240)NFATc3, p(S473)AKT, p(S9)GSK3β, and TRPC3 and -6 proteins, consistent with activation of a positive-feedback loop in which calcium entering through TRPCs activates calcineurin-mediated NFATc3-directed transcription of TRPC genes, leading to more Ca2+ entry. All these changes were markedly reduced in mice lacking TRPC3, -6, and -7. The changes caused by I/R in AAR tissues were matched by those seen after H/R in cardiomyoblasts in all aspects except for p-AKT and p-GSK3β, which were decreased after H/R in cardiomyoblasts instead of increased. TRPC should be promising targets for pharmacologic intervention after cardiac infarcts.

scholarly journals Role of Transient Receptor Potential Channels in Cholecystokinin-Induced Activation of Cultured Vagal Afferent Neurons

Endocrinology ◽  
2010 ◽  
Vol 151 (11) ◽  
pp. 5237-5246 ◽  
Author(s):  
Huan Zhao ◽  
Steven M. Simasko
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cytosolic Calcium ◽  
Membrane Depolarization ◽  
Induced Response ◽  
Trpc Channels ◽  
Afferent Neurons ◽  
Trpv Channels ◽  
Vagal Afferent ◽  
Transient Receptor

Cholecystokinin (CCK), an endogenous brain-gut peptide, is released after food intake and promotes the process of satiation via activation of the vagus nerve. In vitro, CCK increases cytosolic calcium concentrations and produces membrane depolarization in a subpopulation of vagal afferent neurons. However, the specific mechanisms and ionic conductances that mediate these effects remain unclear. In this study we used calcium imaging, electrophysiological measurements, and single cell PCR analysis on cultured vagal afferent neurons to address this issue directly. A cocktail of blockers of voltage-dependent calcium channels (VDCC) failed to block CCK-induced calcium responses. In addition, SKF96365, a compound that blocks both VDCC and the C family of transient receptor potential (TRP) channels, also failed to prevent responses to CCK. Together these results suggest that CCK-induced calcium influx is not subsequent to the membrane depolarization. Ruthenium red, an inhibitor of the TRPV family and TRPA1, blocked both depolarizing responses to CCK and CCK-induced calcium increases, but had no effect on the KCl-induced calcium response. Selective block of TRPV1 and TRPA1 channels with SB366791 and HC030031, respectively, had minor effects on the CCK-induced response. Application of 2-aminoethoxydiphenyl borate, an activator of select TRPV channels but a blocker of several TRPC channels, either had no effect or enhanced the responses to CCK. Further, results from PCR experiments revealed a significant clustering of TRPV2-5 in neurons expressing CCK1 receptors. These observations demonstrate that CCK-induced increases in cytosolic calcium and membrane depolarization of vagal afferent neurons are likely mediated by TRPV channels, excluding TRPV1.

scholarly journals Membrane translocation of TRPC6 channels and endothelial migration are regulated by calmodulin and PI3 kinase activation

2016 ◽  
Vol 113 (8) ◽  
pp. 2110-2115 ◽  
Author(s):  
Pinaki Chaudhuri ◽  
Michael A. Rosenbaum ◽  
Pritam Sinharoy ◽  
Derek S. Damron ◽  
Lutz Birnbaumer ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Oxidation Products ◽  
Site Directed Mutagenesis ◽  
Trpc Channels ◽  
Lipid Oxidation Products ◽  
Transient Receptor

Lipid oxidation products, including lysophosphatidylcholine (lysoPC), activate canonical transient receptor potential 6 (TRPC6) channels leading to inhibition of endothelial cell (EC) migration in vitro and delayed EC healing of arterial injuries in vivo. The precise mechanism through which lysoPC activates TRPC6 channels is not known, but calmodulin (CaM) contributes to the regulation of TRPC channels. Using site-directed mutagenesis, cDNAs were generated in which Tyr99 or Tyr138 of CaM was replaced with Phe, generating mutant CaM, Phe99-CaM, or Phe138-CaM, respectively. In ECs transiently transfected with pcDNA3.1-myc-His-Phe99-CaM, but not in ECs transfected with pcDNA3.1-myc-His-Phe138-CaM, the lysoPC-induced TRPC6-CaM dissociation and TRPC6 externalization was disrupted. Also, the lysoPC-induced increase in intracellular calcium concentration was inhibited in ECs transiently transfected with pcDNA3.1-myc-His-Phe99-CaM. Blocking phosphorylation of CaM at Tyr99 also reduced CaM association with the p85 subunit and subsequent activation of phosphatidylinositol 3-kinase (PI3K). This prevented the increase in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and the translocation of TRPC6 to the cell membrane and reduced the inhibition of EC migration by lysoPC. These findings suggest that lysoPC induces CaM phosphorylation at Tyr99 by a Src family kinase and that phosphorylated CaM activates PI3K to produce PIP3, which promotes TRPC6 translocation to the cell membrane.

Neuropeptide RFRP inhibits the pacemaker activity of terminal nerve GnRH neurons

2013 ◽  
Vol 109 (9) ◽  
pp. 2354-2363 ◽  
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.

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

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.

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

2019 ◽  
Vol 20 (19) ◽  
pp. 4912 ◽  
Author(s):  
Annunziatina Laurino ◽  
Valentina Spinelli ◽  
Manuela Gencarelli ◽  
Valentina Balducci ◽  
Leonardo Dini ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Satellite Cells ◽  
Transient Receptor Potential ◽  
Renin Angiotensin System ◽  
Receptor Potential ◽  
Skeletal Muscle Regeneration ◽  
Trpc Channels ◽  
Direct Role ◽  
Trpc Channel ◽  
Muscle Fibrosis

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.

scholarly journals Emerging Roles of Diacylglycerol-Sensitive TRPC4/5 Channels

Cells ◽  
2018 ◽  
Vol 7 (11) ◽  
pp. 218 ◽  
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.

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

Cells ◽  
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 [...]

scholarly journals TRPC channels: Dysregulation and Ca2+ Mishandling In Ischemic Heart Disease

2019 ◽  
Author(s):  
Debora Falcon ◽  
Isabel Galeano-Otero ◽  
Marta Martín-Bórnez ◽  
María Fernández-Velasco ◽  
Isabel Gallardo-Castillo ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Current Knowledge ◽  
Receptor Potential ◽  
Cardiac Cells ◽  
Membrane Receptors ◽  
Trpc Channels ◽  
Ischemia And Reperfusion ◽  
Sense And Respond ◽  
Transient Receptor

Transient receptor potential canonical (TRPC) channels are ubiquitously expressed in excitable and non-excitable cardiac cells where they sense and respond to a wide variety of physical and chemical stimuli. As other TRP, TRPC may form homo or heterotetrameric ion channel, and they can associate with other membrane receptors and ion channels to regulate intracellular calcium concentration. Dysfunctions of TRPC channels are involved in many types of cardiovascular diseases. Significant increase of the expression of different TRPC isoforms has been observed in different animal model of heart infarcts, and in vitro experimental model of ischemia and reperfusion. TRPC-mediated increase of the intracellular Ca2+ concentration seems required for the activation of signaling pathway that plays minor roles in the healthy heart, but they are more relevant for cardiac responses to ischemia, such as the activation of different factors of transcription and cardiac hypertrophy, fibrosis, and angiogenesis. In this review, we will highlight the current knowledge regarding TRPC implication in different cellular processes related to ischemia and reperfusion, and to heart infarction.

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