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, Motohiro Nishida
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 α 1 -adrenoceptor (α 1 AR)-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 Zn 2+ 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 Zn 2+ influx boosts α 1 AR-stimulated βAR/G s -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 α 1 AR-stimulated Zn 2+ influx and positive inotropic response. Pharmacological enhancement of TRPC6-mediated Zn 2+ influx prevents chronic heart failure progression in mice. Our data demonstrate that TRPC6-mediated Zn 2+ influx with α 1 AR stimulation enhances baroreflex-induced positive inotropy, which may be a new therapeutic strategy for chronic heart failure.