Journal
CURRENT PHARMACEUTICAL DESIGN
Volume 11, Issue 21, Pages 2699-2716Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1381612054546879
Keywords
K-ATP channel; sulfonylurea receptor; inward rectifier; glibenclamide; tolbutamide; repaglinide; potassium channel openers; diazoxide
Categories
Funding
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R25GM056929] Funding Source: NIH RePORTER
- NIGMS NIH HHS [R25 GM056929] Funding Source: Medline
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ATP-sensitive K+ channels, termed K-ATP channels, provide a link between cellular metabolism and membrane electrical activitv in a variety of tissues. Channel isoforms have been identified and arc targets for compounds that both stimulate and inhibit their activity resulting in membrane hyperpolarization and depolarization, respectively. Examples include relaxation of vascular smooth muscle and stimulation of insulin secretion. This article reviews the cloning. molecular biology, and structure of KATP channels, with particular focus oil the SUR1/K(IR)6.2 neuroendocrine channels that are important for the regulation of insulin secretion. We integrate the extensive pharmacologic structure-activity-relationship data on these channels, which defines a bipartite drug binding pocket in the SUR (sulfonylurea receptor), with recent structure-function studies that identify domains of SUR and K(IR)6.2, the channel pore, which are critical for channel assembly, for gating, and for the ligand-receptor interactions that modulate channel activity. The atomic Structure of a sulfonylurea in a protein pocket is used to develop insight into the recognition Of these Compounds. A homology model of KATP channels. based oil VC-MsbA. another member of the ABC protein family, is described and used to position amino acids important for the action of channel openers and blockers within the core of SUR. The model has a central chamber which could serve as a multifaceted binding pocket.
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