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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 upregul...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9606288/
https://www.ncbi.nlm.nih.gov/pubmed/36289215
http://dx.doi.org/10.1038/s41467-022-34194-9
Descripción
Sumario: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.