TRPCチャネルのリン酸化による心血管機能制御 Regulation of Cardiovascular Functions by the Phosphorylation of TRPC Channels

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著者

    • 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
    • 斎木 翔太 SAIKI Shota
    • 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
    • 北島 直幸 [他] KITAJIMA Naoyuki
    • 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 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
    • 佐藤 陽治 SATO Yoji
    • 国立医薬品食品衛生研究所遺伝子細胞医薬部 Division of Cellular and Gene Therapy Products, National Institute of Health Sciences
    • 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

抄録

  Calcium ions (Ca<sup>2+</sup>) play an essential role in homeostasis and the activity of cardiovascular cells. Ca<sup>2+</sup> influx across the plasma membrane induced by neurohumoral factors or mechanical stress elicits physiologically relevant timing and spatial patterns of Ca<sup>2+</sup> signaling, which leads to the activation of various cardiovascular functions, such as muscle contraction, gene expression, and hypertrophic growth of myocytes. A canonical transient receptor potential protein subfamily member, TRPC6, which is activated by diacylglycerol and mechanical stretch, works as an upstream regulator of the Ca<sup>2+</sup> signaling pathway required for pathological hypertrophy. We have recently found that the inhibition of cGMP-selective phosphodiesterase 5 (PDE5) suppresses agonist- and mechanical stretch-induced hypertrophy through inhibition of Ca<sup>2+</sup> influx in rat cardiomyocytes. The inhibition of PDE5 suppressed the increase in frequency of Ca<sup>2+</sup> spikes induced by receptor stimulation or mechanical stretch. Activation of protein kinase G by PDE5 inhibition phosphorylated TRPC6 proteins at Thr<sup>69</sup> and prevented TRPC6-mediated Ca<sup>2+</sup> influx. Substitution of Ala for Thr<sup>69</sup> in TRPC6 abolished the antihypertrophic effects of PDE5 inhibition. These results suggest that phosphorylation and functional suppression of TRPC6 underlies the prevention of cardiac hypertrophy by PDE5 inhibition. As TRPC6 proteins are also expressed in vascular smooth muscle cells and reportedly participate in vascular remodeling, TRPC6 blockade may be an effective therapeutic strategy for preventing pathologic cardiovascular remodeling.<br>

収録刊行物

  • 薬学雑誌. 乙号

    薬学雑誌. 乙号 130(11), 1427-1433, 2010

    公益社団法人 日本薬学会

各種コード

  • NII論文ID(NAID)
    130000451691
  • NII書誌ID(NCID)
    AN00284903
  • 本文言語コード
    JPN
  • ISSN
    0031-6903
  • NDL 記事登録ID
    10893684
  • NDL 雑誌分類
    ZS51(科学技術--薬学)
  • NDL 請求記号
    Z19-411
  • データ提供元
    NDL  J-STAGE 
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