低電位で活性化と不活性化を起こすL型Ca²⁺チャネルCa_V1.3の膜電位依存性特性を決定する分子機構

抄録

Ca_V1.2 (α1C) and Ca_V1.3 (α1D) are pore-forming subunits of cardiac L-type Ca²⁺ channels. We have previously shown that Ca_V1.3 activates and inactivates at more negative voltages than those of Ca_V1.2, thus contributing to the threshold and the duration of the pacemaker action potential in SA nodal cells. To elucidate molecular regions underlying the unique voltage-dependence of Ca_V1.3 in comparison with Ca_V1.2, we examined chimeras of Ca_V1.2 and Ca_V1.3, and found that repeat II of Ca_V1.3 contains a critical domain for the negative shift of its voltage-dependence. In the present study, we further localized the critical regions of the unique voltage-dependence in repeat II of Ca_V1.3. We introduced a series of point mutations in Ca_V1.2 and Ca_V1.2/Ca_V1.3 chimera. The mutant Ca²⁺ channels were transiently expressed in BHK6 cells and analyzed in patch-clamp experiments. As a result, F618L at the outside of three Rs in IIS4 reversed the negative shift of the steady-state inactivation of Ca_V1.2/Ca_V1.3 chimera channel, indicating that F618 is one of regions underlying the voltage-dependence of Ca_V1.3. These results suggest that the difference in a single amino acid in IIS4 between Ca_V1.2 and Ca_V1.3 confers the unique voltage-dependence in cardiac L-type Ca²⁺ channels. [J Physiol Sci. 2006;56 Suppl:S80]