title: Impaired Ca2+ homeostasis is associated with atrial fibrillation in the alpha1D L-type Ca2+ channel KO mouse.
abstract: The novel alpha1D Ca2+ channel together with alpha1C Ca2+ channel contribute to the L-type Ca2+ current (I(Ca-L)) in the mouse supraventricular tissue. However, its functional role in the heart is just emerging. We used the alpha1D gene knockout (KO) mouse to investigate the electrophysiological features, the relative contribution of the alpha1D Ca2+ channel to the global I(Ca-L), the intracellular Ca2+ transient, the Ca2+ handling by the sarcoplasmic reticulum (SR), and the inducibility of atrial fibrillation (AF). In vivo and ex vivo ECG recordings from alpha1D KO mice demonstrated significant sinus bradycardia, atrioventricular block, and vulnerability to AF. The wild-type mice showed no ECG abnormalities and no AF. Patch-clamp recordings from isolated alpha1D KO atrial myocytes revealed a significant reduction of I(Ca-L) (24.5%; P < 0.05). However, there were no changes in other currents such as I(Na), I(Ca-T), I(K), I(f), and I(to) and no changes in alpha1C mRNA levels of alpha1D KO atria. Fura 2-loaded atrial myocytes showed reduced intracellular Ca2+ transient (approximately 40%; P < 0.05) and rapid caffeine application caused a 17% reduction of the SR Ca2+ content (P < 0.05) and a 28% reduction (P < 0.05) of fractional SR Ca2+ release in alpha1D KO atria. In conclusion, genetic deletion of alpha1D Ca2+ channel in mice results in atrial electrocardiographic abnormalities and AF vulnerability. The electrical abnormalities in the alpha1D KO mice were associated with a decrease in the total I(Ca-L) density, a reduction in intracellular Ca2+ transient, and impaired intracellular Ca2+ handling. These findings provide new insights into the mechanism leading to atrial electrical dysfunction in the alpha1D KO mice.
authors.affiliation: Molecular and Cellular Cardiology Program, Veterans Affairs New York Harbor Healthcare System, Brooklyn, NY 11209, USA.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Mancarella
authors.forename: Yuankun
authors.initials: Y
authors.lastname: Yue
authors.forename: Eddy
authors.initials: E
authors.lastname: Karnabi
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Qu
authors.forename: Nabil
authors.initials: N
authors.lastname: El-Sherif
authors.forename: Mohamed
authors.initials: M
authors.lastname: Boutjdir
mesh_terms: D000200:Action Potentials; D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics / Q000378:metabolism*; D054537:Atrioventricular Block / Q000378:metabolism; D001919:Bradycardia / Q000378:metabolism; D002110:Caffeine / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D004562:Electrocardiography; D006325:Heart Atria / Q000378:metabolism; D006706:Homeostasis; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013997:Time Factors
chemical_list: C485995:Cacna1d protein, mouse; D020746:Calcium Channels, L-Type; D012333:RNA, Messenger; D002110:Caffeine
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