Myocardial TRPC6-mediated Zn 2+ influx induces beneficial positive inotropy through β-adrenoceptors

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 -adrenoceptor (α AR)-stimulated cation entry and their upregulatio...

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Published in:Nature communications 2022-10, Vol.13 (1), p.6374
Main Authors: Oda, Sayaka, Nishiyama, Kazuhiro, Furumoto, Yuka, Yamaguchi, Yohei, Nishimura, Akiyuki, Tang, Xiaokang, Kato, Yuri, Numaga-Tomita, Takuro, Kaneko, Toshiyuki, Mangmool, Supachoke, Kuroda, Takuya, Okubo, Reishin, Sanbo, Makoto, Hirabayashi, Masumi, Sato, Yoji, Nakagawa, Yasuaki, Kuwahara, Koichiro, Nagata, Ryu, Iribe, Gentaro, Mori, Yasuo, Nishida, Motohiro
Format: Article
Language:English
Subjects:
Amino Acids - metabolism
Animals
beta-Arrestins - metabolism
Heart Failure - metabolism
Mice
Myocytes, Cardiac - metabolism
Rats
Receptors, Adrenergic, alpha-1 - metabolism
Receptors, Adrenergic, beta - metabolism
TRPC Cation Channels - metabolism
TRPC6 Cation Channel
Zinc - metabolism
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Summary: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 -adrenoceptor (α 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 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 influx boosts α AR-stimulated βAR/G -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 AR-stimulated Zn influx and positive inotropic response. Pharmacological enhancement of TRPC6-mediated Zn influx prevents chronic heart failure progression in mice. Our data demonstrate that TRPC6-mediated Zn influx with α AR stimulation enhances baroreflex-induced positive inotropy, which may be a new therapeutic strategy for chronic heart failure.
ISSN:2041-1723