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J. Biol. Chem., Vol. 281, Issue 44, 33487-33496, November 3, 2006

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

Erik W. Bush¹, David B. Hood, Philip J. Papst, Joseph A. Chapo, Wayne Minobe, Michael R. Bristow, Eric N. Olson^¶2, and Timothy A. McKinsey³

From the Myogen, Inc., Westminster, Colorado 80021, the Division of Cardiology, University of Colorado Health Sciences Center, Denver, Colorado 80262, and the ^¶University of Texas Southwestern Medical Center, Dallas, Texas 75390

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.

Received for publication, June 9, 2006 , and in revised form, August 31, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Supported by grants from the National Institutes of Health, The Donald W. Reynolds Clinical Cardiovascular Research Center, The Robert A. Welch Foundation, and the Texas Advanced Technology Program.

¹ To whom correspondence may be addressed. Tel.: 303-464-5234; Fax: 303-410-6669; E-mail: erik.bush{at}myogen.com. ³ To whom correspondence may be addressed. Tel.: 303-533-1736; Fax: 303-410-6669; E-mail: timothy.mckinsey{at}myogen.com.

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