Insulin secretagogues, sulfonylurea receptors and K(ATP) channels

Curr Pharm Des. 2005;11(21):2699-716. doi: 10.2174/1381612054546879.


ATP-sensitive K+ channels, termed K(ATP) 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 K(ATP) channels, with particular focus on 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 K(ATP) 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.

Publication types

  • Review

MeSH terms

  • ATP-Binding Cassette Transporters / biosynthesis
  • ATP-Binding Cassette Transporters / drug effects*
  • ATP-Binding Cassette Transporters / genetics
  • Animals
  • Binding Sites / drug effects
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Insulin / metabolism*
  • Insulin Secretion
  • Ion Channel Gating / drug effects
  • Ion Channel Gating / physiology
  • KATP Channels
  • Models, Molecular
  • Potassium Channels / biosynthesis
  • Potassium Channels / genetics
  • Potassium Channels, Inwardly Rectifying / biosynthesis
  • Potassium Channels, Inwardly Rectifying / drug effects*
  • Potassium Channels, Inwardly Rectifying / genetics
  • Receptors, Drug / biosynthesis
  • Receptors, Drug / drug effects*
  • Receptors, Drug / genetics
  • Stimulation, Chemical
  • Structure-Activity Relationship
  • Sulfonylurea Compounds / metabolism*
  • Sulfonylurea Receptors


  • ABCC8 protein, human
  • ATP-Binding Cassette Transporters
  • Hypoglycemic Agents
  • Insulin
  • KATP Channels
  • Potassium Channels
  • Potassium Channels, Inwardly Rectifying
  • Receptors, Drug
  • Sulfonylurea Compounds
  • Sulfonylurea Receptors
  • uK-ATP-1 potassium channel

Associated data

  • OMIM/600509
  • OMIM/600935
  • OMIM/600937
  • OMIM/601439