Document Type
Article
Publication Date
10-8-2014
Abstract
The small- and intermediate-conductance Ca 2+ -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 Ca 2+ sensitivity of the SK/IK channels stems from a constitutively bound Ca 2+ -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 Ca 2+ 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.
Recommended Citation
Cui M, Qin G, Yu K, Bowers MS, Zhang M. Targeting the small- and intermediate conductance Ca2+-activated potassium channels: the drug binding pocket at the channel/calmodulin interface. Neurosignals. 2014 Oct. 8;22(2):65-78. PMCID: PMC4390548
DOI:10.1159/000367896
Copyright
S. Karger AG, Basel
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 3.0 License
Included in
Amino Acids, Peptides, and Proteins Commons, Animals Commons, Cardiovascular System Commons, Nervous System Commons, Neurosciences Commons
Comments
This article was originally published in Neurosignals, volume 22, issue 2, in 2014. DOI: 10.1159/000367896