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Perspectives in Diabetes Sulfonylurea Receptors , Ion Channels , and Fruit Flies

Recent studies have identified a high-affinity receptor on the plasma membrane of the p-cell that is specific for all of the sulfonylureas. The most potent secondgeneration drugs, glyburide and glipizide, bind to the receptor and trigger insulin release at nanomolar concentrations. The affinity to the receptor-ligand interaction of all sulfonylureas correlates with their potency as insulin secretagogues, further implicating receptor occupancy with signal transduction. These drugs also inhibit the electrical activity of ATPsensitive K+ channels and K+ efflux through these channels. The channels are also closed by the metabolism of the major insulin secretagogues, glucose and the amino acids, which signal insulin release by increasing the ATP level or the [ATPI-to[ADP] ratio on the cytoplasmic side of the channel. Based on the channel number and the amount of K+ current they pass, it is possible to calculate that these channels control the resting membrane potential of the p-cell. Inactivation of the ATP-inhibitable K+ channel results in a fall in the resting membrane potential, cell depolarization, and influx of extracellular CaZ+ through the voltage-dependent CaZ+ channel. The rise in intracellular free Ca2+ level triggers exocytosis. Thus, it is now possible to link either a stimulus from the metabolism of insulin secretagogues or the sulfonylureas to ionic and electrical events that elicit insulin release. These data also suggest that the sulfonylurea receptor or a closely associated protein is an ATP-sensitive K+ channel. Diabetes 37:847-50, 1988 and delineate how changes in the intracellular free-Ca2+ level ([Ca2+],) are connected to inactivation of this channel. The action of both glucose and sulfonylureas on the ATP-sensitive K+ channel allows speculation about the role of ion channels in signal transduction by sulfonylureas in non-pcells. The literature cited is recent and not all inclusive.