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Myocardial TRPC6-mediated Zn2+ influx induces beneficial positive inotropy through β-adrenoceptors

Author

Listed:
  • Sayaka Oda

    (National Institutes of Natural Sciences
    National Institutes of Natural Sciences
    SOKENDAI (School of Life Science, The Graduate University for Advanced Studies))

  • Kazuhiro Nishiyama

    (Kyushu University)

  • Yuka Furumoto

    (Kyushu University)

  • Yohei Yamaguchi

    (Asahikawa Medical University)

  • Akiyuki Nishimura

    (National Institutes of Natural Sciences
    National Institutes of Natural Sciences
    SOKENDAI (School of Life Science, The Graduate University for Advanced Studies))

  • Xiaokang Tang

    (National Institutes of Natural Sciences
    National Institutes of Natural Sciences
    SOKENDAI (School of Life Science, The Graduate University for Advanced Studies))

  • Yuri Kato

    (Kyushu University)

  • Takuro Numaga-Tomita

    (National Institutes of Natural Sciences
    National Institutes of Natural Sciences
    Shinshu University School of Medicine)

  • Toshiyuki Kaneko

    (Asahikawa Medical University)

  • Supachoke Mangmool

    (Mahidol University)

  • Takuya Kuroda

    (National Institute of Health Sciences)

  • Reishin Okubo

    (Kyushu University)

  • Makoto Sanbo

    (National Institutes of Natural Sciences)

  • Masumi Hirabayashi

    (National Institutes of Natural Sciences)

  • Yoji Sato

    (National Institute of Health Sciences)

  • Yasuaki Nakagawa

    (Kyoto University Graduate School of Medicine)

  • Koichiro Kuwahara

    (Shinshu University School of Medicine)

  • Ryu Nagata

    (Osaka University)

  • Gentaro Iribe

    (Asahikawa Medical University)

  • Yasuo Mori

    (Kyoto University)

  • Motohiro Nishida

    (National Institutes of Natural Sciences
    National Institutes of Natural Sciences
    SOKENDAI (School of Life Science, The Graduate University for Advanced Studies)
    Kyushu University)

Abstract

Baroreflex control of cardiac contraction (positive inotropy) through sympathetic nerve activation is important for cardiocirculatory homeostasis. Transient receptor potential canonical subfamily (TRPC) channels are responsible for α1-adrenoceptor (α1AR)-stimulated cation entry and their upregulation is associated with pathological cardiac remodeling. Whether TRPC channels participate in physiological pump functions remains unclear. We demonstrate that TRPC6-specific Zn2+ influx potentiates β-adrenoceptor (βAR)-stimulated positive inotropy in rodent cardiomyocytes. Deletion of trpc6 impairs sympathetic nerve–activated positive inotropy but not chronotropy in mice. TRPC6-mediated Zn2+ influx boosts α1AR-stimulated βAR/Gs-dependent signaling in rat cardiomyocytes by inhibiting β-arrestin-mediated βAR internalization. Replacing two TRPC6-specific amino acids in the pore region with TRPC3 residues diminishes the α1AR-stimulated Zn2+ influx and positive inotropic response. Pharmacological enhancement of TRPC6-mediated Zn2+ influx prevents chronic heart failure progression in mice. Our data demonstrate that TRPC6-mediated Zn2+ influx with α1AR stimulation enhances baroreflex-induced positive inotropy, which may be a new therapeutic strategy for chronic heart failure.

Suggested Citation

  • Sayaka Oda & Kazuhiro Nishiyama & Yuka Furumoto & Yohei Yamaguchi & Akiyuki Nishimura & Xiaokang Tang & Yuri Kato & Takuro Numaga-Tomita & Toshiyuki Kaneko & Supachoke Mangmool & Takuya Kuroda & Reish, 2022. "Myocardial TRPC6-mediated Zn2+ influx induces beneficial positive inotropy through β-adrenoceptors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34194-9
    DOI: 10.1038/s41467-022-34194-9
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    References listed on IDEAS

    as
    1. Jian Xie & Seung-Kuy Cha & Sung-Wan An & Makoto Kuro-o & Lutz Birnbaumer & Chou-Long Huang, 2012. "Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart," Nature Communications, Nature, vol. 3(1), pages 1-11, January.
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    3. Ashenafi H. Betrie & James A. Brock & Osama F. Harraz & Ashley I. Bush & Guo-Wei He & Mark T. Nelson & James A. Angus & Christine E. Wright & Scott Ayton, 2021. "Zinc drives vasorelaxation by acting in sensory nerves, endothelium and smooth muscle," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    4. Li Xue & Qian Sun & Han Zhao & Xavier Rovira & Siyu Gai & Qianwen He & Jean-Philippe Pin & Jianfeng Liu & Philippe Rondard, 2019. "Rearrangement of the transmembrane domain interfaces associated with the activation of a GPCR hetero-oligomer," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
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