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

Bin Wang, Brad S. Rothberg, Robert Brenner

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

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 β4 subunit and in a human mutation (α D43 4G ) have been linked to epilepsy. Here, we investigate mechanisms underlying the gain-of-function effects of the equiv-alent mouse mutation (α D369G ), its modulation by the β4 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-function ef-fects. D369G causes a greater than twofold increase in the closed-to-open equilibrium constant (6.6e- 7→1.65e- 6 ) and an approximate twofold decrease in Ca 2+ -dissociation constants (closed channel: 11.3→5.2 μ M; open channel: 0.92→0.54 μ M). The β4 subunit inhibits mutant channels through a slowing of activation kinetics. In physiological recording solutions, we established the Ca 2+ dependence of current recruitment during action potential - shaped stimuli. D369G and β4 have opposing effects on BK current recruitment, where D369G reduces and β4 increases K 1/2 (K 1/2 μM: α WT 13.7, α D369G 6.3, α WT /β4 24.8, and α D369G /β4 15.0). Collectively, our results suggest that the D369G enhancement of intrinsic gating and Ca 2+ binding underlies greater contributions of BK current in the sharpening of action potentials for both α and α/β4 channels.

Original languageEnglish (US)
Pages (from-to)283-294
Number of pages12
JournalJournal of General Physiology
Volume133
Issue number3
DOIs
StatePublished - Mar 2009

ASJC Scopus subject areas

  • Physiology

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