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Calcineurin-dependent cardiomyopathy is activated by TRPC in the adult mouse heart

Hiroyuki Nakayama^*, Benjamin J. Wilkin^*, Ilona Bodi and Jeffery D. Molkentin^*,1

^* Department of Pediatrics, University of Cincinnati, Children’s Hospital Medical Center, Cincinnati, Ohio, USA; and

Department of Surgery, University of Cincinnati, Cincinnati, Ohio, USA

¹Correspondence: Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, USA. E-mail: jeff.molkentin{at}cchmc.org

The manner in which Ca²⁺-sensitive signaling proteins are activated in contracting cardiomyocytes is an intriguing theoretical problem given that the cytoplasm is continually bathed with systolic Ca²⁺ concentrations that should maximally activate most Ca²⁺-sensitive signaling kinases and phosphatases. Store-operated Ca²⁺ entry, partially attributed to transient receptor potential (TRP) proteins, can mediate activation of the Ca²⁺-sensitive phosphatase calcineurin in nonexcitable cells. Here we investigated the gain-of-function phenotype associated with TRPC3 expression in the mouse heart using transgenesis to examine the potential role of store-operated Ca²⁺ entry in regulating cardiac calcineurin activation and ensuing hypertrophy/myopathy. Adult myocytes isolated from TRPC3 transgenic mice showed abundant store-operated Ca²⁺ entry that was inhibited with SKF96365 but not verapamil or KB-R7943. Associated with this induction in store-operated Ca²⁺ entry, TRPC3 transgenic mice showed increased calcineurin-nuclear factor of activated T cells (NFAT) activation in vivo, cardiomyopathy, and increased hypertrophy after neuroendocrine agonist or pressure overload stimulation. The cardiomyopathic phenotype and increased hypertrophy after pressure overload stimulation were blocked by targeted disruption of the calcineurin Aß gene. Thus, enhanced store-operated Ca²⁺ entry in the heart can regulate calcineurin-NFAT signaling in vivo, which could secondarily impact the hypertrophic response and cardiomyopathy.—Nakayama, H., Wilkin, B. J., Bodi, I., Molkentin, J. D. Calcineurin-dependent cardiomyopathy is activated by TRPC in the adult mouse heart.

Key Words: signaling • calcium • store-operated • NFAT

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