Insulin Secretagogues, Sulfonylurea Receptors and KATP Channels

Authors: Bryan, J.; Crane, A.; Vila-Carriles, W. H.; Babenko, A. P.; Aguilar-Bryan, L.

Source: Current Pharmaceutical Design, Volume 11, Number 21, August 2005 , pp. 2699-2716(18)

Publisher: Bentham Science Publishers

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Abstract:

ATP-sensitive K+ channels, termed KATP channels, provide a link between cellular metabolism and membrane electrical activity in a variety of tissues. Channel isoforms have been identified and are 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 on the SUR1/KIR6.2 neuroendocrine channels that are important for the regulation of insulin secretion. We integrate the extensive pharmacologic structure-activityrelationship 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 KIR6.2, 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 on 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.

Keywords: katp channel; sulfonylurea receptor; inward rectifier; glibenclamide; tolbutamide; repaglinide; potassium channel openers; diazoxide

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1381612054546879

Affiliations: 1: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston Texas, 77030, USA;

Publication date: 2005-08-01

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Current Pharmaceutical Design publishes timely in-depth reviews covering all aspects of current research in rational drug design. Each issue is devoted to a single major therapeutic area. A Guest Editor who is an acknowledged authority in a therapeutic field has solicits for each issue comprehensive and timely reviews from leading researchers in the pharmaceutical industry and academia.

Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.

Insulin Secretagogues, Sulfonylurea Receptors and KATP Channels

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