ジアシルグリセロール感受性TRPCチャネルを介した心肥大誘導のメカニズム  [in Japanese] Mechanism of Cardiac Hypertrophy <i>via</i> Diacylglycerol-sensitive TRPC Channels  [in Japanese]

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Author(s)

    • 西田 基宏 NISHIDA Motohiro
    • 九州大学大学院薬学研究院薬効安全性学分野 Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University
    • 渡辺 健太 WATANABE Kenta
    • 九州大学大学院薬学研究院薬効安全性学分野 Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University
    • 仲矢 道雄 [他] NAKAYA Michio
    • 九州大学大学院薬学研究院薬効安全性学分野 Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University
    • 黒瀬 等 KUROSE Hitoshi
    • 九州大学大学院薬学研究院薬効安全性学分野 Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University

Abstract

  Activation of Ca<sup>2+</sup> 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<sup>2+</sup> targets specifically decode the alteration of intracellular Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>i</sub>) on the background of the rhythmic Ca<sup>2+</sup> increases required for muscle contraction. In excitable cardiomyocytes, changes in the frequency or amplitude of Ca<sup>2+</sup> transients evoked by Ca<sup>2+</sup> influx-induced Ca<sup>2+</sup> 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<sup>2+</sup> 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<sub>q</sub> protein-coupled receptor stimulation. DAG-mediated membrane depolarization through activation of TRPC3/TRPC6 channels increases the frequency of Ca<sup>2+</sup> 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<sub>12</sub> 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.<br>

Journal

  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 130(3), 295-302, 2010

    The Pharmaceutical Society of Japan

Codes

  • NII Article ID (NAID)
    130000259511
  • NII NACSIS-CAT ID (NCID)
    AN00284903
  • Text Lang
    JPN
  • ISSN
    0031-6903
  • NDL Article ID
    10588273
  • NDL Source Classification
    ZS51(科学技術--薬学)
  • NDL Call No.
    Z19-411
  • Data Source
    NDL  J-STAGE 
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