TRPC1 channels are critical for hypertrophic signaling in the heart.
BACKGROUND
Cardiac muscle adapts to increase workload by altering cardiomyocyte size and function resulting in cardiac hypertrophy. G protein-coupled receptor signaling is known to govern the hypertrophic response through the regulation of ion channel activity and downstream signaling in failing cardiomyocytes.


OBJECTIVE
Transient receptor potential canonical (TRPC) channels are G protein-coupled receptor operated channels previously implicated in cardiac hypertrophy. Our objective of this study is to better understand how TRPC channels influence cardiomyocyte calcium signaling.


RESULTS
Here, we used whole cell patch clamp of adult cardiomyocytes to show upregulation of a nonselective cation current reminiscent of TRPC channels subjected to pressure overload. This TRPC current corresponds to the increased TRPC channel expression noted in hearts of mice subjected to pressure overload. Importantly, we show that mice lacking TRPC1 channels are missing this putative TRPC current. Moreover, Trpc1(-)(/)(-) mice fail to manifest evidence of maladaptive cardiac hypertrophy and maintain preserved cardiac function when subjected to hemodynamic stress and neurohormonal excess. In addition, we provide a mechanistic basis for the protection conferred to Trpc1(-)(/)(-) mice as mechanosensitive signaling through calcineurin/NFAT, mTOR and Akt is altered in Trpc1(-)(/)(-) mice.


CONCLUSIONS
From these studies, we suggest that TRPC1 channels are critical for the adaptation to biomechanical stress and TRPC dysregulation leads to maladaptive cardiac hypertrophy and failure.
Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
Malini
M
Seth
Zhu-Shan
ZS
Zhang
Lan
L
Mao
Victoria
V
Graham
Jarrett
J
Burch
Jonathan
J
Stiber
Leonidas
L
Tsiokas
Michelle
M
Winn
Joel
J
Abramowitz
Howard A
HA
Rockman
Lutz
L
Birnbaumer
Paul
P
Rosenberg
D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D058570:TOR Serine-Threonine Kinases; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D019703:Calcineurin