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 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.