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

Sayaka Oda, Kazuhiro Nishiyama, Yuka Furumoto, Yohei Yamaguchi, Akiyuki Nishimura, Xiaokang Tang, Yuri Kato, Takuro Numaga-Tomita, Toshiyuki Kaneko, Supachoke Mangmool, Takuya Kuroda, Reishin Okubo, Makoto Sanbo, Masumi Hirabayashi, Yoji Sato, Yasuaki Nakagawa, Koichiro Kuwahara, Ryu Nagata, Gentaro Iribe, Yasuo Mori and Motohiro Nishida ()
Additional contact information
Sayaka Oda: National Institutes of Natural Sciences
Kazuhiro Nishiyama: Kyushu University
Yuka Furumoto: Kyushu University
Yohei Yamaguchi: Asahikawa Medical University
Akiyuki Nishimura: National Institutes of Natural Sciences
Xiaokang Tang: National Institutes of Natural Sciences
Yuri Kato: Kyushu University
Takuro Numaga-Tomita: National Institutes of Natural Sciences
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

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34194-9

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