Myocardial TRPC6-mediated Zn Influx Induces Beneficial Positive Inotropy Through β-adrenoceptors

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Oct 26

PMID 36289215

Authors

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

Affiliations

Soon will be listed here.

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-adrenoceptor (αAR)-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 αAR-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 αAR-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 αAR stimulation enhances baroreflex-induced positive inotropy, which may be a new therapeutic strategy for chronic heart failure.

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