Oda S.Nishiyama K.Furumoto Y.Yamaguchi Y.Nishimura A.Tang X.Kato Y.Numaga-Tomita T.Kaneko T.Mangmool S.Kuroda T.Okubo R.Sanbo M.Hirabayashi M.Sato Y.Nakagawa Y.Kuwahara K.Nagata R.Iribe G.Mori Y.Nishida M.Mahidol University2023-06-182023-06-182022-12-01Nature Communications Vol.13 No.1 (2022)https://repository.li.mahidol.ac.th/handle/123456789/83519Baroreflex 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/Gs-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.Biochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1038/s41467-022-34194-92-s2.0-851406305512041172336289215