Journal article
Mechanism of increased open probability by a mutation of the BK channel
Journal of neurophysiology, Vol.96(3), pp.1507-1516
09/2006
DOI: 10.1152/jn.00461.2006
PMID: 16738211
Abstract
A missense mutation (D434G) has recently been identified in the alpha 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 alpha subunit, modulation by the regulatory beta4 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 alpha subunits, the mutant channel spent less time in a long-lived closed state. Co-expression of the beta4 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.
Details
- Title: Subtitle
- Mechanism of increased open probability by a mutation of the BK channel
- Creators
- Ana Díez-Sampedro - Department of Neurology, Yale University School of Medicine, New Haven, CT 06520-8018, USA. ana.diez-sampedro@yale.eduWilliam R SilvermanJocelyn F BautistaGeorge B Richerson
- Resource Type
- Journal article
- Publication Details
- Journal of neurophysiology, Vol.96(3), pp.1507-1516
- Publisher
- United States
- DOI
- 10.1152/jn.00461.2006
- PMID
- 16738211
- ISSN
- 0022-3077
- eISSN
- 1522-1598
- Language
- English
- Date published
- 09/2006
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Neurosurgery
- Record Identifier
- 9984020755502771
Metrics
11 Record Views