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Mechanism of Increased Open Probability by a Mutation of the BK Channel

¹Departments of Neurology, ²Molecular Biophysics and Biochemistry, and ⁴Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut; ³Department of Neurology, Cleveland Clinic, Cleveland, Ohio; and ⁵Veteran's Affairs Medical Center, West Haven, Connecticut

Submitted 1 May 2006; accepted in final form 25 May 2006

A missense mutation (D434G) has recently been identified in the subunit of the human large-conductance calcium-activated potassium (BK) channel. Interestingly, although the mutation causes an increase in open probability, individuals that carry the mutation have epilepsy and/or paroxysmal dyskinesia, disorders of increased brain excitability. To define the mechanisms of the mutation, we have used recordings from single channels and measurement of macroscopic conductances to examine the gating of the subunit, modulation by the regulatory 4 subunit, and the effect of Mg²⁺ on channel properties. Although there was relatively little difference in open dwell times for the mutant and wild-type subunits, the mutant channel spent less time in a long-lived closed state. Co-expression of the 4 subunit caused the wild-type channel to be less sensitive to calcium at low Ca²⁺ concentrations but had little effect on the mutant channel, further accentuating the difference between the wild-type and the mutant channels. In the absence of Ca²⁺, there was no difference in Mg²⁺ or voltage sensitivity of the mutant and wild-type channels, whereas in 2 mM Ca²⁺, the mutant channel had greater open probability at every Mg²⁺ concentration tested. We conclude that the D434G mutation modifies Ca²⁺-dependent activation, but we find no evidence of a direct effect on activation by Mg²⁺ or voltage. The resulting enhancement of BK channel function leads to an increase in brain excitability, possibly due to more rapid repolarization of action potentials.

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