Cardiac L-type Ca²⁺ channels and Ca²⁺ signaling: Regulation and molecular mechanisms.

Abstract

L-type Ca²⁺ channel serves as a primary step in the regulation of Ca²⁺ signaling in cardiac E-C coupling. We have shown in cardiac myocytes that L-type Ca²⁺ channels serve as a sensor and regulator of the SR Ca²⁺ content via CICR-dependent CDI (Ca²⁺-dependent inactivation) of L-type Ca²⁺ channels to ensure the efficacy of I_Ca to trigger CICR during APs. In atria, the down-regulation of L-type Ca²⁺ channels, in response to excess mechanical and electrical stimuli, is involved in arrhythmia such as atrial fibrillation. Two types of L-type Ca²⁺ channel pore-forming α subunits, Ca_V1.2 and Ca_V1.3, are expressed in atria. Aiming at elucidating the molecular mechanism of the regulation of atrial L-type Ca²⁺ channels, we studied the gating properties and their regulatory mechanisms of Ca_V1.2 and Ca_V1.3. The voltage-dependence of activation and inactivation of Ca_V1.3, were shifted to lower voltages, compared to those of Ca_V1.2, by approximately -15 mV. The voltage-dependent inactivation kinetics of Ca_V1.3 was slower than that of Ca_V1.2. Such voltage-dependence and kinetics of inactivation of Ca_V1.3 may contribute to maintain the threshold and duration of pacemaker action potential in atrial myocytes. The critical molecular region and the molecular complex involved in the unique gating properties and the regulation of atrial L-type Ca²⁺ channels, with respect to their roles in the fine-tuning of Ca²⁺ signaling, will be further discussed. [J Physiol Sci. 2007;57 Suppl:S13]