title: A knock-in mouse model of N-terminal R420W mutation of cardiac ryanodine receptor exhibits arrhythmogenesis with abnormal calcium dynamics in cardiomyocytes.
abstract: Cardiac ryanodine receptor gene (RyR2) mutations cause fatal arrhythmogenic diseases such as catecholaminergic polymorphic ventricular tachycardia and arrhythmogenic right ventricular cardiomyopathy. The N-terminal region of RyR2 is one of the hot spots for mutations. In this study, we investigated cardiac phenotypes of a knock-in mouse model carrying R420W mutation of RyR2. The N-terminal R420W mutation has already been found in juvenile sudden death cadavers of unrelated families. The depolarization-induced Ca(2+) transient amplitude was significantly lower in cardiomyocytes from RyR2(R420W/R420W) mice compared with wild-type mice. The time to peak of the Ca(2+) transient was significantly increased in RyR2(R420W/R420W) mice. Furthermore, the prolonged decay time from the peak of the Ca(2+) transient was detected in RyR2(R420W/R420W) mice. ECG telemetry revealed that various types of arrhythmias were induced in RyR2(R420W/R420W) mice in response to administration of caffeine and adrenaline. The mutant mice showed high occurrences of arrhythmias in response to heart stimulants compared with wild-type mice. These findings suggest that R420W mutation impairs depolarization-induced Ca(2+) oscillation in cardiomyocytes, which possibly results in sudden death due to stress-induced arrhythmias.
authors.affiliation: Department of Legal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan. Electronic address: noku@hyo-med.ac.jp.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Okudaira
authors.affiliation: Laboratory of Veterinary Pathophysiology and Animal Health, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. Electronic address: akuwam@mail.ecc.u-tokyo.ac.jp.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kuwahara
authors.affiliation: Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan. Electronic address: hiratayu@hyo-med.ac.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hirata
authors.affiliation: Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan. Electronic address: yoku@hyo-med.ac.jp.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Oku
authors.affiliation: Department of Legal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan. Electronic address: hnishio@hyo-med.ac.jp.
authors.forename: Hajime
authors.initials: H
authors.lastname: Nishio
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D019943:Amino Acid Substitution; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D004195:Disease Models, Animal; D004837:Epinephrine / Q000494:pharmacology; D015870:Gene Expression; D055879:Gene Knock-In Techniques; D017136:Ion Transport; D008297:Male; D051379:Mice; D009154:Mutation; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D017434:Protein Structure, Tertiary; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; C000592748:ryanodine receptor 2. mouse; D002110:Caffeine; D002118:Calcium; D004837:Epinephrine
keywords: Arrhythmia; Calcium; Model mouse; Sudden death