Impaired Ca2+ homeostasis is associated with atrial fibrillation in the α1D L-type Ca2+ channel KO mouse

Abstract

The novel α1D Ca2+ channel together with α1C Ca2+ channel contribute to the L-type Ca2+ current ( ICa-L) in the mouse supraventricular tissue. However, its functional role in the heart is just emerging. We used the α1D gene knockout (KO) mouse to investigate the electrophysiological features, the relative contribution of the α1D Ca2+ channel to the global ICa-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 α1D 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 α1D KO atrial myocytes revealed a significant reduction of ICa-L (24.5%; P < 0.05). However, there were no changes in other currents such as INa, ICa-T, IK, If, and Ito and no changes in α1C mRNA levels of α1D KO atria. Fura 2-loaded atrial myocytes showed reduced intracellular Ca2+ transient (∼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 α1D KO atria. In conclusion, genetic deletion of α1D Ca2+ channel in mice results in atrial electrocardiographic abnormalities and AF vulnerability. The electrical abnormalities in the α1D KO mice were associated with a decrease in the total ICa-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 α1D KO mice.