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

• Published in: Nature communications 2022-10, Vol.13 (1), p.6374-6374, Article 6374
• Main Authors: Oda, Sayaka, Nishiyama, Kazuhiro, Furumoto, Yuka, Yamaguchi, Yohei, Nishimura, Akiyuki, Tang, Xiaokang, Kato, Yuri, Numaga-Tomita, Takuro, Kaneko, Toshiyuki, Mangmool, Supachoke, Kuroda, Takuya, Okubo, Reishin, Sanbo, Makoto, Hirabayashi, Masumi, Sato, Yoji, Nakagawa, Yasuaki, Kuwahara, Koichiro, Nagata, Ryu, Iribe, Gentaro, Mori, Yasuo, Nishida, Motohiro
• Format: Article
• Language: English
• Subjects: 13; 13/109; 13/95; 14; 14/19; 38; 38/61; 631/443/592/75/230; 692/4019/592/2727; Adrenergic receptors; Amino acids; Arrestin; Baroreceptors; Cardiomyocytes; Channels; Congestive heart failure; Heart failure; Homeostasis; Humanities and Social Sciences; Internalization; Mice; multidisciplinary; Muscle contraction; Nerves; Receptors (physiology); Reflexes; Science; Science (multidisciplinary); Sympathetic nerves; Transient receptor potential proteins; Zinc
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34194-9

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. Baroreflex control of cardiac contractility is essential to maintain cardiocirculatory homeostasis. Here, Oda et al show that α1 adrenoceptor-stimulated Zn2+ entry through TRPC6 channels boosts β adrenoceptor-dependent myocardial positive inotropy.