TRPC1 Channels Are Critical for Hypertrophic Signaling in the Heart

Overview

Journal Circ Res

Specialty Cardiology & Vascular Diseases

Date 2009 Oct 3

PMID 19797170

Citations 105

Authors

Malini Seth

Zhu-Shan Zhang

Lan Mao

Victoria Graham

Jarrett Burch

Jonathan Stiber

Leonidas Tsiokas

Michelle Winn

Joel Abramowitz

Howard A Rockman

Lutz Birnbaumer

Paul Rosenberg

Affiliations

Soon will be listed here.

Abstract

Rationale: Cardiac muscle adapts to increase workload by altering cardiomyocyte size and function resulting in cardiac hypertrophy. G protein-coupled receptor signaling is known to govern the hypertrophic response through the regulation of ion channel activity and downstream signaling in failing cardiomyocytes.

Objective: Transient receptor potential canonical (TRPC) channels are G protein-coupled receptor operated channels previously implicated in cardiac hypertrophy. Our objective of this study is to better understand how TRPC channels influence cardiomyocyte calcium signaling.

Methods And Results: Here, we used whole cell patch clamp of adult cardiomyocytes to show upregulation of a nonselective cation current reminiscent of TRPC channels subjected to pressure overload. This TRPC current corresponds to the increased TRPC channel expression noted in hearts of mice subjected to pressure overload. Importantly, we show that mice lacking TRPC1 channels are missing this putative TRPC current. Moreover, Trpc1(-)(/)(-) mice fail to manifest evidence of maladaptive cardiac hypertrophy and maintain preserved cardiac function when subjected to hemodynamic stress and neurohormonal excess. In addition, we provide a mechanistic basis for the protection conferred to Trpc1(-)(/)(-) mice as mechanosensitive signaling through calcineurin/NFAT, mTOR and Akt is altered in Trpc1(-)(/)(-) mice.

Conclusions: From these studies, we suggest that TRPC1 channels are critical for the adaptation to biomechanical stress and TRPC dysregulation leads to maladaptive cardiac hypertrophy and failure.

Citing Articles

Mechanosensitive ion channels in glaucoma pathophysiology.

Garcia-Sanchez J, Lin D, Liu W Vision Res. 2024; 223:108473.

PMID: 39180975 PMC: 11398070. DOI: 10.1016/j.visres.2024.108473.

Cardiac Hypertrophy: From Pathophysiological Mechanisms to Heart Failure Development.

Caturano A, Vetrano E, Galiero R, Salvatore T, Docimo G, Epifani R Rev Cardiovasc Med. 2024; 23(5):165.

PMID: 39077592 PMC: 11273913. DOI: 10.31083/j.rcm2305165.

High-content method for mechanosignaling studies using IsoStretcher technology and quantitative Ca imaging applied to Piezo1 in cardiac HL-1 cells.

Merten A, Scholer U, Guo Y, Linsenmeier F, Martinac B, Friedrich O Cell Mol Life Sci. 2024; 81(1):140.

PMID: 38485771 PMC: 10940437. DOI: 10.1007/s00018-024-05159-6.

Canonical transient receptor potential channel 1 aggravates myocardial ischemia-and-reperfusion injury by upregulating reactive oxygen species.

Zhang H, Zhang M, Tian W, Quan W, Song F, Liu S J Pharm Anal. 2024; 13(11):1309-1325.

PMID: 38174113 PMC: 10759261. DOI: 10.1016/j.jpha.2023.08.018.

Interactions between calcium regulatory pathways and mechanosensitive channels in airways.

Yao Y, Borkar N, Zheng M, Wang S, Pabelick C, Vogel E Expert Rev Respir Med. 2023; 17(10):903-917.

PMID: 37905552 PMC: 10872943. DOI: 10.1080/17476348.2023.2276732.

References

Wen Z, Han L, Bamburg J, Shim S, Ming G, Zheng J . BMP gradients steer nerve growth cones by a balancing act of LIM kinase and Slingshot phosphatase on ADF/cofilin. J Cell Biol. 2007; 178(1):107-19. PMC: 2064427. DOI: 10.1083/jcb.200703055. View

Dyachenko V, Husse B, Rueckschloss U, Isenberg G . Mechanical deformation of ventricular myocytes modulates both TRPC6 and Kir2.3 channels. Cell Calcium. 2008; 45(1):38-54. DOI: 10.1016/j.ceca.2008.06.003. View

Liu X, Bandyopadhyay B, Singh B, Groschner K, Ambudkar I . Molecular analysis of a store-operated and 2-acetyl-sn-glycerol-sensitive non-selective cation channel. Heteromeric assembly of TRPC1-TRPC3. J Biol Chem. 2005; 280(22):21600-6. DOI: 10.1074/jbc.C400492200. View

Kiyonaka S, Kato K, Nishida M, Mio K, Numaga T, Sawaguchi Y . Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound. Proc Natl Acad Sci U S A. 2009; 106(13):5400-5. PMC: 2664023. DOI: 10.1073/pnas.0808793106. View

Strubing C, Krapivinsky G, Krapivinsky L, Clapham D . TRPC1 and TRPC5 form a novel cation channel in mammalian brain. Neuron. 2001; 29(3):645-55. DOI: 10.1016/s0896-6273(01)00240-9. View

Williams R, Rosenberg P . Calcium-dependent gene regulation in myocyte hypertrophy and remodeling. Cold Spring Harb Symp Quant Biol. 2003; 67:339-44. DOI: 10.1101/sqb.2002.67.339. View

Sadoshima J, Xu Y, Slayter H, Izumo S . Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell. 1993; 75(5):977-84. DOI: 10.1016/0092-8674(93)90541-w. View

Berridge M . Microdomains and elemental events in calcium signalling. Cell Calcium. 1996; 20(2):95-6. DOI: 10.1016/s0143-4160(96)90098-6. View

Montell C, Birnbaumer L, Flockerzi V . The TRP channels, a remarkably functional family. Cell. 2002; 108(5):595-8. DOI: 10.1016/s0092-8674(02)00670-0. View

10.

McKinsey T, Kass D . Small-molecule therapies for cardiac hypertrophy: moving beneath the cell surface. Nat Rev Drug Discov. 2007; 6(8):617-35. DOI: 10.1038/nrd2193. View

11.

Ni Y, Wang N, Cao D, Sachan N, Morris D, Gerard R . FoxO transcription factors activate Akt and attenuate insulin signaling in heart by inhibiting protein phosphatases. Proc Natl Acad Sci U S A. 2007; 104(51):20517-22. PMC: 2154463. DOI: 10.1073/pnas.0610290104. View

12.

Dyachenko V, Christ A, Gubanov R, Isenberg G . Bending of z-lines by mechanical stimuli: an input signal for integrin dependent modulation of ion channels?. Prog Biophys Mol Biol. 2008; 97(2-3):196-216. DOI: 10.1016/j.pbiomolbio.2008.02.007. View

13.

Rosenberg P, Hawkins A, Stiber J, Shelton J, Hutcheson K, Bassel-Duby R . TRPC3 channels confer cellular memory of recent neuromuscular activity. Proc Natl Acad Sci U S A. 2004; 101(25):9387-92. PMC: 438986. DOI: 10.1073/pnas.0308179101. View

14.

Hofmann T, Obukhov A, Schaefer M, Harteneck C, Gudermann T, Schultz G . Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature. 1999; 397(6716):259-63. DOI: 10.1038/16711. View

15.

Onohara N, Nishida M, Inoue R, Kobayashi H, Sumimoto H, Sato Y . TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy. EMBO J. 2006; 25(22):5305-16. PMC: 1636614. DOI: 10.1038/sj.emboj.7601417. View

16.

Greka A, Navarro B, Oancea E, Duggan A, Clapham D . TRPC5 is a regulator of hippocampal neurite length and growth cone morphology. Nat Neurosci. 2003; 6(8):837-45. DOI: 10.1038/nn1092. View

17.

Dietrich A, Kalwa H, Fuchs B, Grimminger F, Weissmann N, Gudermann T . In vivo TRPC functions in the cardiopulmonary vasculature. Cell Calcium. 2007; 42(2):233-44. DOI: 10.1016/j.ceca.2007.02.009. View

18.

Yang T, Yu R, Agadir A, Gao G, Campos-Gonzalez R, Tournier C . Integration of protein kinases mTOR and extracellular signal-regulated kinase 5 in regulating nucleocytoplasmic localization of NFATc4. Mol Cell Biol. 2008; 28(10):3489-501. PMC: 2423171. DOI: 10.1128/MCB.01847-07. View

19.

Faul C, Asanuma K, Yanagida-Asanuma E, Kim K, Mundel P . Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton. Trends Cell Biol. 2007; 17(9):428-37. DOI: 10.1016/j.tcb.2007.06.006. View

20.

Winn M, Conlon P, Lynn K, Farrington M, Creazzo T, Hawkins A . A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science. 2005; 308(5729):1801-4. DOI: 10.1126/science.1106215. View