TY - JOUR
T1 - Myocardial TRPC6-mediated Zn2+ influx induces beneficial positive inotropy through β-adrenoceptors
AU - Oda, Sayaka
AU - Nishiyama, Kazuhiro
AU - Furumoto, Yuka
AU - Yamaguchi, Yohei
AU - Nishimura, Akiyuki
AU - Tang, Xiaokang
AU - Kato, Yuri
AU - Numaga-Tomita, Takuro
AU - Kaneko, Toshiyuki
AU - Mangmool, Supachoke
AU - Kuroda, Takuya
AU - Okubo, Reishin
AU - Sanbo, Makoto
AU - Hirabayashi, Masumi
AU - Sato, Yoji
AU - Nakagawa, Yasuaki
AU - Kuwahara, Koichiro
AU - Nagata, Ryu
AU - Iribe, Gentaro
AU - Mori, Yasuo
AU - Nishida, Motohiro
N1 - Funding Information:
We thank Dr. Mi Xinya and Yuya Taniguchi for support with cardiomyocyte isolation and recombinant AAV construction. We also thank the Spectrography and Bioimaging Facility (NIBB Core Research Facilities). We thank Mitchell Arico and Gabrielle White Wolf, Ph.D., from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript. This work was supported by JST CREST Grant Number JPMJCR2024 (20348438), JSPS KAKENHI (Grant Numbers JP20H05512, JP20H03673, JP21H05269, JP22H02772, JP22K19395, JP21K15338, and JP22H04814), and AMED (Grant Number JP22ama121031 and JP21ek0109509). This work was supported in part by the National Research Foundation of Korea (NRF) funded by the Korean government (MSIP) (2017K1A1A2004511) and a grant of Planned Collaborative Project from the National Institute for Physiological Sciences (NIPS; 21-212).
Funding Information:
We thank Dr. Mi Xinya and Yuya Taniguchi for support with cardiomyocyte isolation and recombinant AAV construction. We also thank the Spectrography and Bioimaging Facility (NIBB Core Research Facilities). We thank Mitchell Arico and Gabrielle White Wolf, Ph.D., from Edanz ( https://jp.edanz.com/ac ) for editing a draft of this manuscript. This work was supported by JST CREST Grant Number JPMJCR2024 (20348438), JSPS KAKENHI (Grant Numbers JP20H05512, JP20H03673, JP21H05269, JP22H02772, JP22K19395, JP21K15338, and JP22H04814), and AMED (Grant Number JP22ama121031 and JP21ek0109509). This work was supported in part by the National Research Foundation of Korea (NRF) funded by the Korean government (MSIP) (2017K1A1A2004511) and a grant of Planned Collaborative Project from the National Institute for Physiological Sciences (NIPS; 21-212).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-34194-9
DO - 10.1038/s41467-022-34194-9
M3 - Article
C2 - 36289215
AN - SCOPUS:85140630551
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6374
ER -