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[Mechanism of cardiac hypertrophy via diacylglycerol-sensitive TRPC channels]

Motohiro Nishida1, Kenta Watanabe, Michio Nakaya

  • 1Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Japan. nishida@phar.kyushu-u.ac.jp

Yakugaku Zasshi : Journal of the Pharmaceutical Society of Japan
|March 2, 2010
PubMed

Insights

Canonical transient receptor potential (TRPC) channels, specifically TRPC3 and TRPC6, mediate cardiac hypertrophy by increasing calcium spike frequency. Inhibiting these TRPC channels blocks hypertrophy, suggesting they are therapeutic targets for heart failure.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Cell Signaling

Background:

  • Cardiac hypertrophy is linked to altered cardiomyocyte calcium (Ca2+) signaling.
  • The precise mechanisms by which Ca2+ signals are decoded for hypertrophy remain unclear.
  • Changes in Ca2+ transient frequency or amplitude may encode hypertrophic signals.

Purpose of the Study:

  • To investigate the role of diacylglycerol (DAG)-responsive canonical transient receptor potential (TRPC) channels in mediating cardiac hypertrophy.
  • To elucidate the signaling pathways involved in G(q) protein-coupled receptor-induced cardiomyocyte depolarization and hypertrophy.
  • To explore TRPC3 and TRPC6 as potential therapeutic targets for heart failure.

Main Methods:

  • Investigated TRPC3 and TRPC6 channel activation by G(q) protein-coupled receptor stimulation.
  • Assessed the impact of TRPC channel activation on cardiomyocyte Ca2+ oscillations and calcineurin signaling.
  • Utilized pharmacological inhibition of TRPC3 and TRPC6 to evaluate their role in agonist-induced hypertrophic responses.
  • Examined the effect of G(12) family proteins on TRPC6 expression in response to hypertrophic agonists.

Main Results:

  • Activation of TRPC3 and TRPC6 channels mediates membrane depolarization induced by G(q) protein-coupled receptor stimulation.
  • DAG-mediated depolarization via TRPC3/TRPC6 increases Ca2+ spike frequency, activating calcineurin-dependent pathways.
  • Inhibition of TRPC3 or TRPC6 completely abolished agonist-induced hypertrophic responses, indicating they form functional heterotetrameric channels.
  • Hypertrophic agonists upregulate TRPC6 expression via G(12) proteins, amplifying hypertrophic signaling.

Conclusions:

  • TRPC3 and TRPC6 channels are critical mediators of cardiac hypertrophy.
  • These TRPC channels represent a novel therapeutic target for preventing or treating heart failure progression.
  • Understanding TRPC channel function provides insights into cardiomyocyte Ca2+ signaling and hypertrophic pathways.

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