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Suppression of Rad leads to arrhythmogenesis via PKA-mediated phosphorylation of ryanodine receptor activity in the heart
Authors:Hiroyuki Yamakawa  Mitsushige Murata  Tomoyuki Suzuki  Hirotaka Yada  Hideyuki Ishida  Yoshiyasu Aizawa  Takeshi Adachi  Kaichiro Kamiya  Keiichi Fukuda
Institution:1. Department of Cardiology, School of Medicine, Keio University, Tokyo, Japan;2. Department of Laboratory Medicine, School of Medicine, Keio University, Tokyo, Japan;3. Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan;4. Department of Cardiology, First Internal Medicine, National Defense Medical College, Saitama, Japan;5. Department of Physiology, Tokai University School of Medicine, Kanagawa, Japan
Abstract:Ras-related small G-protein Rad plays a critical role in generating arrhythmias via regulation of the L-type Ca2+ channel (LTCC). The aim was to demonstrate the role of Rad in intracellular calcium homeostasis by cardiac-Specific dominant-negative suppression of Rad. Transgenic (TG) mice overexpressing dominant-negative mutant Rad (S105N Rad TG) were generated. To measure intracellular Ca2+ concentration (Ca2+]i), we recorded Ca2+]i transients and Ca2+ sparks from isolated cardiomyocytes using confocal microscopy. The mean Ca2+]i transient amplitude was significantly increased in S105N Rad TG cardiomyocytes, compared with control littermate mouse cells. The frequency of Ca2+ sparks was also significantly higher in TG cells than in control cells, although there were no significant differences in amplitude. The sarcoplasmic reticulum Ca2+ content was not altered in the S105N Rad TG cells, as assessed by measuring caffeine-induced Ca2+]i transient. In contrast, phosphorylation of Ser2809 on the cardiac ryanodine receptor (RyR2) was significantly enhanced in TG mouse hearts compared with controls. Additionally, the Rad-mediated RyR2 phosphorylation was regulated via a direct interaction of Rad with protein kinase A (PKA).
Keywords:Rad (Ras associated with diabetes)  Excitation&ndash  contraction (EC) coupling (ECC)  Ryanodine receptor  Ca2+ imaging  PKA signaling
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