Myocardial TRPC6-mediated Zn<sup>2+</sup> influx induces beneficial positive inotropy through β-adrenoceptors
Issued Date
2022-12-01
Resource Type
eISSN
20411723
Scopus ID
2-s2.0-85140630551
Pubmed ID
36289215
Journal Title
Nature Communications
Volume
13
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Nature Communications Vol.13 No.1 (2022)
Suggested Citation
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. Myocardial TRPC6-mediated Zn<sup>2+</sup> influx induces beneficial positive inotropy through β-adrenoceptors. Nature Communications Vol.13 No.1 (2022). doi:10.1038/s41467-022-34194-9 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/83519
Title
Myocardial TRPC6-mediated Zn<sup>2+</sup> influx induces beneficial positive inotropy through β-adrenoceptors
Author's Affiliation
Graduate School of Medicine
Graduate School of Engineering
National Institutes of Natural Sciences - Exploratory Research Center on Life and Living Systems
Osaka University
National Institutes of Natural Sciences - National Institute for Physiological Sciences
The Graduate University for Advanced Studies
Mahidol University
Kyushu University
Asahikawa Medical University
National Institute of Health Sciences Tokyo
Shinshu University Faculty of Medicine
Graduate School of Engineering
National Institutes of Natural Sciences - Exploratory Research Center on Life and Living Systems
Osaka University
National Institutes of Natural Sciences - National Institute for Physiological Sciences
The Graduate University for Advanced Studies
Mahidol University
Kyushu University
Asahikawa Medical University
National Institute of Health Sciences Tokyo
Shinshu University Faculty of Medicine
Other Contributor(s)
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 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.