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¹ Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229
² Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140

Correspondence to Robert Brenner: brennerr{at}uthscsa.edu

Concerted depolarization and Ca²⁺ rise during neuronal action potentials activate large-conductance Ca²⁺- 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 (_D434G) have been linked to epilepsy. Here, we investigate mechanisms underlying the gain-of-function effects of the equivalent mouse mutation (_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 Ca²⁺-dependent gating largely account for the gain-of-function effects. D369G causes a greater than twofold increase in the closed-to-open equilibrium constant (6.6e^–71.65e^–6) and an approximate twofold decrease in Ca²⁺-dissociation constants (closed channel: 11.35.2 µM; open channel: 0.920.54 µM). The β4 subunit inhibits mutant channels through a slowing of activation kinetics. In physiological recording solutions, we established the Ca²⁺ 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: _WT 13.7, _D369G 6.3, _WT/β4 24.8, and _D369G/β4 15.0). Collectively, our results suggest that the D369G enhancement of intrinsic gating and Ca²⁺ binding underlies greater contributions of BK current in the sharpening of action potentials for both and /β4 channels.

© 2009 Wang et al.
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