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

Baroreflex control of cardiac contractility is essential to maintain cardiocirculatory homeostasis. Here, Oda et al show that alpha 1 adrenoceptor-stimulated Zn2+ entry through TRPC6 channels boosts beta adrenoceptor-dependent myocardial positive inotropy. 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 alpha(1)-adrenoceptor (alpha(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 Zn2+ influx potentiates beta-adrenoceptor (beta AR)-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 alpha(1)AR-stimulated beta AR/G(s)-dependent signaling in rat cardiomyocytes by inhibiting beta-arrestin-mediated beta AR internalization. Replacing two TRPC6-specific amino acids in the pore region with TRPC3 residues diminishes the alpha(1)AR-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 alpha(1)AR stimulation enhances baroreflex-induced positive inotropy, which may be a new therapeutic strategy for chronic heart failure.