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Recently we have described a splice variant of the L-type Ca²⁺ channel (α_1C,86) in which 80 amino acids (1572–1651) of the conventional α_1C,77 were substituted by another 81 amino acids due to alternative splicing of exons 40–42. Ba²⁺ current (I_Ba) through α_1C,86 exhibited faster inactivation kinetics, was strongly voltage-dependent, and had no Ca²⁺-dependent inactivation. An oligonucleotide-directed segment substitution and expression of the mutated channels in Xenopus oocytes were used to study the molecular determinants for gating of the channel within the 80-amino acid domain. Replacement of segments 1572–1598 or 1595–1652 of the "slow" α_1C,77 channel with the respective segments of the "fast" α_1C,86 gave rise to rapidly inactivating α_1C,86-like channel isoforms. We found that replacement of either motifs ¹⁵⁷²IKTEG¹⁵⁷⁶ or¹⁶⁰⁰LLDQV¹⁶⁰⁴ of α_1C,77 with the respective sequences of α_1C …