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

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/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 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.