[Mechanism of cardiac hypertrophy via diacylglycerol-sensitive TRPC channels].
Activation of Ca(2+) signaling in cardiomyocytes induced by receptor stimulation or mechanical stress has been implicated in the development of cardiac hypertrophy. However, it is still unclear how intracellular Ca(2+) targets specifically decode the alteration of intracellular Ca(2+) concentration ([Ca(2+)](i)) on the background of the rhythmic Ca(2+) increases required for muscle contraction. In excitable cardiomyocytes, changes in the frequency or amplitude of Ca(2+) transients evoked by Ca(2+) influx-induced Ca(2+) release have been suggested to encode signals for induction of hypertrophy, and a partial depolarization of plasma membrane by receptor stimulation will increase the frequency of Ca(2+) oscillations. We found that activation of diacylglycerol (DAG)-responsive canonical transient receptor potential (TRPC) subfamily channels (TRPC3 and TRPC6) mediate membrane depolarization induced by G(q) protein-coupled receptor stimulation. DAG-mediated membrane depolarization through activation of TRPC3/TRPC6 channels increases the frequency of Ca(2+) spikes, leading to activation of calcineurin-dependent signaling pathways. Inhibition of either TRPC3 or TRPC6 completely suppressed agonist-induced hypertrophic responses, suggesting that TRPC3 and TRPC6 form heterotetramer channels. Furthermore, we found that hypertrophic agonists increase the expression of TRPC6 proteins through activation of G(12) family proteins, leading to amplification of DAG-mediated hypertrophic signaling in cardiomyocytes. As heart failure proceeds through cardiac hypertrophy, TRPC3/TRPC6 channels may be a new therapeutic target for heart failure.
Nishida
Motohiro
M
Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Japan. nishida@phar.kyushu-u.ac.jp
Watanabe
Kenta
K
Nakaya
Michio
M
Kurose
Hitoshi
H
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D006332:Cardiomegaly / Q000235:genetics*; D004075:Diglycerides; D015195:Drug Design; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D050052:TRPC Cation Channels / Q000502:physiology*; D000074287:TRPC6 Cation Channel
D004075:Diglycerides; D043562:Receptors, G-Protein-Coupled; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; D002118:Calcium