期刊
NATURE GENETICS
卷 37, 期 7, 页码 733-738出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng1585
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资金
- NHLBI NIH HHS [R01 HL070393] Funding Source: Medline
The large conductance calcium- sensitive potassium ( BK) channel is widely expressed in many organs and tissues, but its in vivo physiological functions have not been fully defined. Here we report a genetic locus associated with a human syndrome of coexistent generalized epilepsy and paroxysmal dyskinesia on chromosome 10q22 and show that a mutation of the a subunit of the BK channel causes this syndrome. The mutant BK channel had a markedly greater macroscopic current. Single- channel recordings showed an increase in open-channel probability due to a three- to fivefold increase in Ca2+ sensitivity. We propose that enhancement of BK channels in vivo leads to increased excitability by inducing rapid repolarization of action potentials, resulting in generalized epilepsy and paroxysmal dyskinesia by allowing neurons to fire at a faster rate. These results identify a gene that is mutated in generalized epilepsy and paroxysmal dyskinesia and have implications for the pathogenesis of human epilepsy, the neurophysiology of paroxysmal movement disorders and the role of BK channels in neurological disease.
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