Calcineurin-dependent cardiomyopathy is activated by TRPC in the adult mouse heart.
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 Abeta 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
Hiroyuki
H
Department of Pediatrics, University of Cincinnati, Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Wilkin
Benjamin J
BJ
Bodi
Ilona
I
Molkentin
Jeffery D
JD
D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000209:etiology; D009202:Cardiomyopathies / Q000209:etiology*; D002478:Cells, Cultured; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D050052:TRPC Cation Channels / Q000502:physiology*
D050778:NFATC Transcription Factors; D050052:TRPC Cation Channels; D019703:Calcineurin; D002118:Calcium