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Calcineurin‐dependent cardiomyopathy is activated by TRPC in the adult mouse heart
Author(s) -
Nakayama Hiroyuki,
Wilkin Benjamin J.,
Bodi Ilona,
Molkentin Jeffery D.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-5560com
Subject(s) - calcineurin , trpc3 , nfat , trpc , endocrinology , microbiology and biotechnology , phosphatase , medicine , pressure overload , myocyte , muscle hypertrophy , biology , chemistry , transplantation , transient receptor potential channel , receptor , phosphorylation , cardiac hypertrophy
The manner in which Ca 2+ ‐sensitive signaling proteins are activated in contracting cardiomyocytes is an intriguing theoretical problem given that the cytoplasm is continually bathed with systolic Ca 2+ concentrations that should maximally activate most Ca 2+ ‐sensitive signaling kinases and phosphatases. Store‐operated Ca 2+ entry, partially attributed to transient receptor potential (TRP) proteins, can mediate activation of the Ca 2+ ‐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 Ca 2+ entry in regulating cardiac calcineurin activation and ensuing hypertrophy/myopathy. Adult myocytes isolated from TRPC3 transgenic mice showed abundant store‐operated Ca 2+ entry that was inhibited with SKF96365 but not verapamil or KB‐R7943. Associated with this induction in store‐operated Ca 2+ 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 Aβ gene. Thus, enhanced store‐operated Ca 2+ 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. FASEB J. 20, 1660–1670 (2006)