期刊
NEUROSIGNALS
卷 22, 期 2, 页码 65-78出版社
KARGER
DOI: 10.1159/000367896
关键词
Small- and intermediate-conductance Ca2+-activated potassium channels; Small-molecule positive modulators; Structure-based drug discovery; Ataxia; Alcohol use disorders; Parkinson's disease
资金
- American Heart Association [13SDG16150007]
- National Institutes of Health [S10RR027411, P50AA022537]
- Alcohol Beverage Medical Research Foundation
- National High Technology Research and Development Program of China [2012AA020301, 2012AA01A305]
- Chinese Academy of Sciences Project [KSZD-EW-L09-4]
The small- and intermediate-conductance Ca2+-activated potassium (SK/IK) channels play important roles in the regulation of excitable cells in both the central nervous and cardiovascular systems. Evidence from animal models has implicated SK/IK channels in neurological conditions such as ataxia and alcohol use disorders. Further, genome-wide association studies have suggested that cardiovascular abnormalities such as arrhythmias and hypertension are associated with single nucleotide polymorphisms that occur within the genes encoding the SK/IK channels. The Ca2+ sensitivity of the SK/IK channels stems from a constitutively bound Ca2+-binding protein: calmodulin. Small-molecule positive modulators of SK/IK channels have been developed over the past decade, and recent structural studies have revealed that the binding pocket of these positive modulators is located at the interface between the channel and calmodulin. SK/IK channel positive modulators can potentiate channel activity by enhancing the coupling between Ca2+ sensing via calmodulin and mechanical opening of the channel. Here, we review binding pocket studies that have provided structural insight into the mechanism of action for SK/IK channel positive modulators. These studies lay the foundation for structure-based drug discovery efforts that can identify novel SK/IK channel positive modulators. (C) 2014 S. Karger AG, Basel
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