Abstract 164: Microdomain Specific Effects of Transient Receptor Potential Channels on Pathological Cardiac Hypertrophy and Myocyte Contractility

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Catherine A Makarewich ◽  
Hongyu Zhang ◽  
Hui Gao ◽  
Robert N Correll ◽  
Jason M Duran ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Trpc Channels ◽  
Ec Coupling ◽  
Transient Receptor ◽  
Myocyte Contractility ◽  
Signaling Domains ◽  
Ca2 Channels

Hypothesis: Ca2+ influx through transient receptor potential canonical (TRPC) channels and L-type Ca2+ channels (LTCCs) within caveolin-3 (Cav3) stabilized signaling microdomains provide a unique source of Ca2+ to activate pathologic cardiac hypertrophy through calcineurin (Cn)-mediated nuclear factor of activated T-cells (NFAT) signaling. We suggest that a distinct and separate population of TRPC channels localized in excitation-contraction (EC) coupling microdomains may have potent effects on myocyte contractility independent of Cav3 signaling domains. Methods and Results: Membrane localization studies and immunohistochemistry show that TRPC channels and LTCCs co-localize to Cav3 signaling microdomains. To explore a role for these caveolae based Ca2+ channels in the initiation of Cn-NFAT signaling we used an adenoviral NFAT-GFP reporter in cultured adult feline myocytes (AFMs). Infecting AFMs with ad-TRPC3 dramatically increased NFAT translocation, which was inhibited with dominant negative ad-dnTRPC6. Expression of a Cav3 targeted LTCC blocker (ad-Cav-Rem) reduced NFAT translocation while a targeted LTCC activator (ad-Cav-β2a) significantly increased NFAT activation. Neither LTCC modulator had significant effects on Ca2+ current or contractility in AFMs but we found that the expression of TRPC3 reduced myocyte contractility and induced spontaneous Ca2+ spark activity that was exacerbated by the DAG activator OAG. Moreover, dnTRPC6 blocked spontaneous Ca2+ sparks even in the presence of OAG. Immunohistochemistry analysis revealed the presence of TRPC channels in transverse tubules, consistent with the idea that they could have direct effects on EC coupling microdomains. Conclusions: Our data show that TRPC channels and LTCCs co-localize to Cav3 signaling domains where they generate a unique Ca2+ microenvironment that directly regulates Cn-NFAT signaling. Our findings also suggest that a separate and distinct population of TRPC channels within EC coupling microdomains cause reduced myocyte contractility by inducing SR Ca2+ leak and Ca2+ spark activity.

Expression and relative abundance of short transient receptor potential channels in the rat renal microcirculation

2004 ◽  
Vol 286 (3) ◽  
pp. F546-F551 ◽  
Author(s):  
Carie S. Facemire ◽  
Peter J. Mohler ◽  
William J. Arendshorst
Keyword(s):  
Relative Abundance ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cell Types ◽  
Calcium Entry ◽  
Transient Receptor Potential Channels ◽  
Trpc Channels ◽  
Renal Microcirculation ◽  
Resistance Vessels ◽  
Transient Receptor

In the resistance vessels of the renal microcirculation, store- and/or receptor-operated calcium entry contribute to the rise in vascular smooth muscle cell (VSMC) intracellular calcium concentration in response to vasoconstrictor hormones. Short transient receptor potential (TRPC) channels are widely expressed in mammalian tissues and are proposed mediators of voltage-independent cation entry in multiple cell types, including VSMCs. The seven members of the TRPC gene family (TRPC1-7) encode subunit proteins that are thought to form homo- and heterotetrameric channels that are differentially regulated depending on their subunit composition. In the present study, we demonstrate the relative abundance of TRPC mRNA and protein in freshly isolated rat renal resistance vessels, glomeruli, and aorta. TRPC1, 3, 4, 5, and 6 mRNA and protein were detected in both renal resistance vessels and aorta, whereas TRPC2 and TRPC7 mRNA were not expressed. TRPC1, 3, 5, and 6 protein was present in glomeruli. TRPC3 and TRPC6 protein levels were significantly greater in the renal resistance vessels, about six- to eightfold higher than in aorta. These data suggest that TRPC3 and TRPC6 may play a role in mediating voltage-independent calcium entry in renal resistance vessels that is functionally distinct from that in aorta.

scholarly journals Dynamic NHERF interaction with TRPC4/5 proteins is required for channel gating by diacylglycerol

2016 ◽  
Vol 114 (1) ◽  
pp. E37-E46 ◽  
Author(s):  
Ursula Storch ◽  
Anna-Lena Forst ◽  
Franziska Pardatscher ◽  
Serap Erdogmus ◽  
Maximilian Philipp ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Activation Mechanism ◽  
Binding Motif ◽  
Trpc Channels ◽  
Channel Activity ◽  
C Terminus ◽  
Potential Channels ◽  
Transient Receptor

The activation mechanism of the classical transient receptor potential channels TRPC4 and -5 via the Gq/11 protein-phospholipase C (PLC) signaling pathway has remained elusive so far. In contrast to all other TRPC channels, the PLC product diacylglycerol (DAG) is not sufficient for channel activation, whereas TRPC4/5 channel activity is potentiated by phosphatidylinositol 4,5-bisphosphate (PIP2) depletion. As a characteristic structural feature, TRPC4/5 channels contain a C-terminal PDZ-binding motif allowing for binding of the scaffolding proteins Na+/H+ exchanger regulatory factor (NHERF) 1 and 2. PKC inhibition or the exchange of threonine for alanine in the C-terminal PDZ-binding motif conferred DAG sensitivity to the channel. Altogether, we present a DAG-mediated activation mechanism for TRPC4/5 channels tightly regulated by NHERF1/2 interaction. PIP2 depletion evokes a C-terminal conformational change of TRPC5 proteins leading to dynamic dissociation of NHERF1/2 from the C terminus of TRPC5 as a prerequisite for DAG sensitivity. We show that NHERF proteins are direct regulators of ion channel activity and that DAG sensitivity is a distinctive hallmark of TRPC channels.

Abstract 138: Transient Receptor Potential Channel C1 Deficiency Protects the Murine Heart from Pressure Overload

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Malini Seth ◽  
Zhu-Shan Zhang ◽  
Lan Mao ◽  
Jarrett Burch ◽  
Victoria Graham ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Transient Receptor Potential ◽  
Pressure Overload ◽  
Receptor Potential ◽  
Receptor Activation ◽  
Trpc Channels ◽  
Loss Of Function ◽  
Aortic Banding ◽  
Trpc1 Channels ◽  
Transient Receptor

Transient receptor potential canonical (TRPC) channels are non-selective cation channels that are activated in response to G-protein coupled receptor activation, depletion of internal stores and mechanical stretch. Recent reports suggest that cardiac TRPC channels mediate calcineurin dependent cardiac hypertrophy, yet few details exist as to the mechanism for activation of these channels. Here, we provide evidence that TRPC1 channels are the dominant TRPC channel in mouse cardiomyocytes and cardiac TRPC1 protein expression is augmented by seven fold following thoracic aortic banding (TAC). In addition, we provide the first loss of function studies to show that mice lacking TRPC1 channels developed significantly less cardiac hypertrophy following pressure overload induced by thoracic aortic banding suggesting that TRPC1 may confer deleterious calcium entry. Whole cell voltage clamp studies of isolated adult cardiomyocytes reveal a non-selective cation current that is induced by pressure overload that is absent in TRPC1−/− cardiomyocytes and in which TRP blockers such as gadolinium, 2-amino biphenyl boric acid and SKF96365 inhibit the TAC induced current. Finally, neonatal cardiomyocytes lacking functional TRPC1 display reduced TRPC current in response to cell stretch or angiotensin-II; the functional consequence of which includes reduced calcium oscillation frequency and reduced BNP expression. These results provide the first loss of function evidence for TRPC1 channels in cardiac hypertrophy and implicate TRPC1 as a stretch activated channel.

scholarly journals Effects of Ginger and its Pungent Constituents on Transient Receptor Potential Channels

2017 ◽  
Vol 112 (3) ◽  
pp. 250a
Author(s):  
Young-Soo Kim ◽  
Chan Sik Hong ◽  
Sang Weon Lee ◽  
Joo Hyun Nam ◽  
Byung Joo Kim
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Potential Channels ◽  
Transient Receptor

scholarly journals Novel role of transient receptor potential vanilloid 2 in the regulation of cardiac performance

2014 ◽  
Vol 306 (4) ◽  
pp. H574-H584 ◽  
Author(s):  
Jack Rubinstein ◽  
Valerie M. Lasko ◽  
Sheryl E. Koch ◽  
Vivek P. Singh ◽  
Vinicius Carreira ◽  
...  
Keyword(s):  
Vascular Function ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Wild Type ◽  
Transient Receptor ◽  
Systolic And Diastolic Function ◽  
Myocyte Contractility

Transient receptor potential cation channels have been implicated in the regulation of cardiovascular function, but only recently has our laboratory described the vanilloid-2 subtype (TRPV2) in the cardiomyocyte, though its exact mechanism of action has not yet been established. This study tests the hypothesis that TRPV2 plays an important role in regulating myocyte contractility under physiological conditions. Therefore, we measured cardiac and vascular function in wild-type and TRPV2−/− mice in vitro and in vivo and found that TRPV2 deletion resulted in a decrease in basal systolic and diastolic function without affecting loading conditions or vascular tone. TRPV2 stimulation with probenecid, a relatively selective TRPV2 agonist, caused an increase in both inotropy and lusitropy in wild-type mice that was blunted in TRPV2−/− mice. We examined the mechanism of TRPV2 inotropy/lusitropy in isolated myocytes and found that it modulates Ca2+ transients and sarcoplasmic reticulum Ca2+ loading. We show that the activity of this channel is necessary for normal cardiac function and that there is increased contractility in response to agonism of TRPV2 with probenecid.

What Evolutionary Evidence Implies About the Identity of the Mechanoelectrical Couplers in Vascular Smooth Muscle Cells

Physiology ◽  
2021 ◽  
Vol 36 (5) ◽  
pp. 292-306
Author(s):  
Heather A. Drummond
Keyword(s):  
Transient Receptor Potential ◽  
Molecular Model ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Potential Channels ◽  
Transient Receptor ◽  
Paradigm Shifting ◽  
G Protein Coupled ◽  
Evolutionary Role

Loss of pressure-induced vasoconstriction increases susceptibility to renal and cerebral vascular injury. Favored paradigms underlying initiation of the response include transient receptor potential channels coupled to G protein-coupled receptors or integrins as transducers. Degenerin channels may also mediate the response. This review addresses the 1) evolutionary role of these molecules in mechanosensing, 2) limitations to identifying mechanosensitive molecules, and 3) paradigm shifting molecular model for a VSMC mechanosensor.

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