Canonical Transient Receptor Potential Channels Promote Cardiomyocyte Hypertrophy through Activation of Calcineurin Signaling*

The calcium/calmodulin-dependent phosphatase calcineurin plays a central role in the control of cardiomyocyte hypertrophy in response to pathological stimuli. Although calcineurin is present at high levels in normal heart, its activity appears to be unaffected by calcium during the course of a cardiac cycle. The mechanism(s) whereby calcineurin is selectively activated by calcium under pathological conditions has remained unclear. Here, we demonstrate that diverse signals for cardiac hypertrophy stimulate expression of canonical transient receptor potential (TRPC) channels. TRPC consists of a family of seven membrane-spanning nonselective cation channels that have been implicated in the nonvoltage-gated influx of calcium in response to G protein-coupled receptor signaling, receptor tyrosine kinase signaling, and depletion of internal calcium stores. TRPC3 expression is up-regulated in multiple rodent models of pathological cardiac hypertrophy, whereas TRPC5 expression is induced in failing human heart. We demonstrate that TRPC promotes cardiomyocyte hypertrophy through activation of calcineurin and its downstream effector, the nuclear factor of activated T cells transcription factor. These results define a novel role for TRPC channels in the control of cardiac growth, and suggest that a TRPC-derived pool of calcium contributes to selective activation of calcineurin in diseased heart.

[1]  B. Tombal,et al.  Calcium store contents control the expression of TRPC1, TRPC3 and TRPV6 proteins in LNCaP prostate cancer cell line. , 2006, Cell calcium.

[2]  J. Putney,et al.  Mechanism of Inhibition of TRPC Cation Channels by 2-Aminoethoxydiphenylborane , 2005, Molecular Pharmacology.

[3]  J. Putney.  Physiological mechanisms of TRPC activation , 2005, Pflügers Archiv.

[4]  Bernd Nilius,et al.  TRP Channels in Disease , 2005, Science's STKE.

[5]  J. Soboloff,et al.  A Functional Link between Store-operated and TRPC Channels Revealed by the 3,5-Bis(trifluoromethyl)pyrazole Derivative, BTP2* , 2005, Journal of Biological Chemistry.

[6]  G. Barritt,et al.  TRPs as mechanosensitive channels , 2005, Nature Cell Biology.

[7]  A. Kurosky,et al.  TRPC1 forms the stretch-activated cation channel in vertebrate cells , 2005, Nature Cell Biology.

[8]  B. Harrison,et al.  The CRM1 Nuclear Export Receptor Controls Pathological Cardiac Gene Expression , 2004, Molecular and Cellular Biology.

[9]  J. Soboloff,et al.  Sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) gene silencing and remodeling of the Ca2+ signaling mechanism in cardiac myocytes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[10]  P. Thistlethwaite,et al.  Bosentan inhibits transient receptor potential channel expression in pulmonary vascular myocytes. , 2004, American journal of respiratory and critical care medicine.

[11]  J. Molkentin,et al.  Calcium-calcineurin signaling in the regulation of cardiac hypertrophy. , 2004, Biochemical and biophysical research communications.

[12]  J. Putney,et al.  Obligatory Role of Src Kinase in the Signaling Mechanism for TRPC3 Cation Channels* , 2004, Journal of Biological Chemistry.

[13]  I. Fantozzi,et al.  Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[14]  R. Bassel-Duby,et al.  TRPC3 channels confer cellular memory of recent neuromuscular activity. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[15]  B. DeDecker,et al.  Chemical genetics to identify NFAT inhibitors: Potential of targeting calcium mobilization in immunosuppression , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[16]  M. Hoth,et al.  Potent Inhibition of Ca2+ Release-activated Ca2+ Channels and T-lymphocyte Activation by the Pyrazole Derivative BTP2* , 2004, Journal of Biological Chemistry.

[17]  E. Olson,et al.  A small molecular activator of cardiac hypertrophy uncovered in a chemical screen for modifiers of the calcineurin signaling pathway. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[18]  H. Kwan,et al.  Regulation of canonical transient receptor potential isoform 3 (TRPC3) channel by protein kinase G. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[19]  E. Olson,et al.  Cardiac hypertrophy: the good, the bad, and the ugly. , 2003, Annual review of physiology.

[20]  Rick B. Vega,et al.  The role of modulatory calcineurin-interacting proteins in calcineurin signaling. , 2003, Trends in cardiovascular medicine.

[21]  Antonio Riccio,et al.  mRNA distribution analysis of human TRPC family in CNS and peripheral tissues. , 2002, Brain research. Molecular brain research.

[22]  H. Debaix,et al.  Involvement of TRPC in the abnormal calcium influx observed in dystrophic (mdx) mouse skeletal muscle fibers , 2002, The Journal of cell biology.

[23]  R. Marchase,et al.  Capacitative Calcium Entry Contributes to Nuclear Factor of Activated T-cells Nuclear Translocation and Hypertrophy in Cardiomyocytes* , 2002, The Journal of Biological Chemistry.

[24]  G. Crabtree,et al.  NFAT Signaling Choreographing the Social Lives of Cells , 2002, Cell.

[25]  Julie A. Wilkins,et al.  Potent Inhibition of NFAT Activation and T Cell Cytokine Production by Novel Low Molecular Weight Pyrazole Compounds* , 2001, The Journal of Biological Chemistry.

[26]  Rick B. Vega,et al.  Myocyte-enriched calcineurin-interacting protein, MCIP1, inhibits cardiac hypertrophy in vivo , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[27]  E. Olson,et al.  Independent Signals Control Expression of the Calcineurin Inhibitory Proteins MCIP1 and MCIP2 in Striated Muscles , 2000, Circulation research.

[28]  E. Olson,et al.  Decoding calcium signals involved in cardiac growth and function , 2000, Nature Medicine.

[29]  Rick B. Vega,et al.  A Protein Encoded within the Down Syndrome Critical Region Is Enriched in Striated Muscles and Inhibits Calcineurin Signaling* , 2000, The Journal of Biological Chemistry.

[30]  T. Gudermann,et al.  Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol , 1999, Nature.

[31]  Jeffrey Robbins,et al.  A Calcineurin-Dependent Transcriptional Pathway for Cardiac Hypertrophy , 1998, Cell.

[32]  J. Sadoshima,et al.  The cellular and molecular response of cardiac myocytes to mechanical stress. , 1997, Annual review of physiology.

[33]  R. Cody,et al.  Echocardiographic characterization of left ventricular adaptation in a genetically determined heart failure rat model. , 1995, American heart journal.

[34]  D. Levy,et al.  Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. , 1990, The New England journal of medicine.