1. Myocardial TRPC6-mediated Zn 2+ influx induces beneficial positive inotropy through β-adrenoceptors.
- Author
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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, and Nishida M
- Subjects
- Rats, Animals, Mice, TRPC6 Cation Channel, Myocytes, Cardiac metabolism, Receptors, Adrenergic, beta metabolism, Receptors, Adrenergic, alpha-1 metabolism, beta-Arrestins metabolism, Amino Acids metabolism, Zinc metabolism, TRPC Cation Channels metabolism, Heart Failure metabolism
- 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
1 -adrenoceptor (α1 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 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 α1 AR-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 α1 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 α1 AR stimulation enhances baroreflex-induced positive inotropy, which may be a new therapeutic strategy for chronic heart failure., (© 2022. The Author(s).)- Published
- 2022
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