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.
Bush
Erik W
EW
Myogen, Inc., Westminster, Colorado 80021, USA. erik.bush@myogen.com
Hood
David B
DB
Papst
Philip J
PJ
Chapo
Joseph A
JA
Minobe
Wayne
W
Bristow
Michael R
MR
Olson
Eric N
EN
McKinsey
Timothy A
TA
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D050778:NFATC Transcription Factors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D013830:Thiadiazoles / Q000494:pharmacology
C476308:4-methyl-4'-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-1,2,3-thiadiazole-5-carboxanilide; D000813:Anilides; D050778:NFATC Transcription Factors; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; C491780:TRPC5 protein, human; D013830:Thiadiazoles; D019703:Calcineurin