Mechanism of increased BK channel activation from a channel mutation that causes epilepsy.

ABSTRACT: Concerted depolarization and Ca(2+) rise during neuronal action potentials activate large-conductance Ca(2+)- and voltage-dependent K(+) (BK) channels, whose robust K(+) currents increase the rate of action potential repolarization. Gain-of-function BK channels in mouse knockout of the inhibitory beta 4 subunit and in a human mutation (alpha(D434G)) have been linked to epilepsy. Here, we investigate mechanisms underlying the gain-of-function effects of the equivalent mouse mutation (alpha(D369G)), its modulation by the beta 4 subunit, and potential consequences of the mutation on BK currents during action potentials. Kinetic analysis in the context of the Horrigan-Aldrich allosteric gating model revealed that changes in intrinsic and Ca(2+)-dependent gating largely account for the gain-of-

SUBMITTER: Wang B 

PROVIDER: S-EPMC2654085 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature