Molecular and Electrophysiological Differences in the L-Type Ca²⁺ Channel of the Atrium and Ventricle of Rat Hearts

Abstract

he L-type Ca 2+ channel expressed in cardiac muscle plays an important role in determining the intracellular Ca 2+ and thus the action potential duration of cardiomyocytes. 1 Although Ca 2+ overload is a major cause of myocardial cell injury, 2 blocking this channel could be either beneficial or detrimental. In fact, the available L-type Ca 2+ channel blockers should be useful for treating several types of cardiac arrhythmias, but might cause negative inotropic effects that lead to pump failure. A T-type Ca 2+ channel blocker, mibefradil, has shown potential for preventing tachycardia-induced atrial fibrillation remodeling, 3 although its underlying mechanism of prevention remains unclear. Because the T-type Ca 2+ channel blockers are one of the "atrium specific Ca 2+ channel blockers", regional differences in the L-type Ca 2+ channel blocker, if any, would open a new paradigm for controlling regional intracellular Ca 2+ .The function of the L-type Ca 2+ channel is characterized by its main subunit, 1C (Cacna1c) (Cav1.2), and also the auxiliary subunits 2 (Cacna2d) and (Cacnb). However, there are few reports investigating regional differences in Ca 2+ channel composition. Because previous studies have focused on regional or developmental differences of a single subunit, 4,5 it would be inappropriate to discuss regional differences of the L-type Ca 2+ channel with special reference to the relative expression of the composite subunits. In the present study, to determine whether the composition of the L-type Ca 2+ channel is identical throughout the heart, we analyzed both the distribution of the mRNAs and proteins that comprise the L-type Ca 2+ channel and its electrophysiological properties in rat atria and ventricles. Methods mRNA Analysis and Ribonuclease Protection AssayHearts were harvested from 10-week-old female SpragueDawley (SD) rats. For mRNA analysis, the excised hearts were divided into the sinus-node, the right atrium, the left atrium, the intraventricular septum, the epicardial side of the left ventricular free wall, the endocardial side, the left Methods and ResultsTo determine whether the L-type Ca 2+ channel is identical throughout the heart, the distribution of the mRNAs and proteins comprising the L-type Ca 2+ channel and its electrophysiological properties were analyzed in rat atria and ventricles. The mRNA of 2 -2 (Cacna2d2) was more abundantly expressed in the atrium (~5-fold) than in the ventricle. In contrast, 1C (Cacna1c) (Cav1.2) mRNA was significantly less abundant in the atrium. The level of the 1C (Cacna1c) (Cav1.2) protein was decreased (~0.5-fold) and that of 2 -1 (Cacna2d1) was increased (~2-fold) in the atrium compared with the ventricle. Although the peak ICa,L density showed no significant differences, voltage dependence of inactivation and activation of the current showed a more depolarized shift in the atrium than in the ventricle. Conclusion These results indicate that in the rat heart the L-type Ca 2+ channel differs between the atrium and ventricle with regard to gene expre...

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