Mechanism of cardiac hypertrophy via diacylglycerol-sensitive TRPC channels

Research output: Contribution to journalReview article

3 Citations (Scopus)

Abstract

Activation of Ca2+ 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 Ca2+ concentration ([Ca2+]i) on the background of the rhythmic Ca2+ increases required for muscle contraction. In excitable cardiomyocytes, changes in the frequency or amplitude of Ca 2+ transients evoked by Ca2+ 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 Ca2+ oscillations. We found that activation of diacylglycerol (DAG)-responsive canonical transient receptor potential (TRPC) subfamily channels (TRPC3 and TRPC6) mediate membrane depolarization induced by Gq protein-coupled receptor stimulation. DAG-mediated membrane depolarization through activation of TRPC3/TRPC6 channels increases the frequency of Ca2+ 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 G12 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.

Original languageEnglish
Pages (from-to)295-302
Number of pages8
JournalYakugaku Zasshi
Volume130
Issue number3
DOIs
Publication statusPublished - Mar 2010

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

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