Assembly of KATP channels from SUR1 and KIR6.2

cretion, and other cellular functions. Unexpectedly, islets Adenosine 5 -triphosphate-sensitive potassium (KATP) from Sur1KO mice are refractory to GLP-1 and GIP, channels are unique combinations of potassium inward gastrointestinal peptides known to potentiate glucoserectifiers (KIR6.x) and sulfonylurea receptors (SURs), induced insulin secretion by elevating cAMP. The normembers of the transport ATPase or ATP-binding casmal potentiation of secretion by cAMP is not affected sette superfamily. In pancreatic -cells, KATP channels by PKA inhibitors, thus the results argue KATP channels couple metabolism to membrane electrical activity and participate in cAMP sensing in cells, possibly via direct regulate insulin secretion by modulating the cell resting interactions with the recently discovered guanine nucleomembrane potential and thus the activity of voltagetide, exchange proteins activated by cAMP, termed gated Ca2 channels. Early studies defined the stoichiomEpacs or cAMP-GEFs. Thus, although KATP channels etry of the -cell channel as (SUR1/KIR6.2)4; more recent are missing and [Ca2 ]i is elevated, disrupting the enterwork has centered on defining functionally important oinsular axis removes a major stimulus for insulin release domains and interactions within the channel, for examallowing KATPKO mice to remain normoglycemic. ple, for drug binding and regulation of gating. Work done in the mid-1990s identified mutations in human BIBLIOGRAPHY Sur1 or KIR6.2 genes that altered or abolished KATP chanAguilar-Bryan L, Bryan J: Molecular biology of adenosine triphosnel activity and produced mild or severe recessive forms phate-sensitive potassium channels. Endocr Rev 20:101–135, 1999 of persistent hyperinsulinemic hypoglycemia of infancy, Babenko AP, Gonzalez G, Bryan J: Pharmaco-topology of sulfonylPHHI. Point mutations that affect regulation by ADP/ urea receptors. Separate domains of the regulatory subunits of KATP channel isoforms are required for selective interaction with K ATP are known, while nonsense and splice site mutations channel openers. J Biol Chem 275:717–720, 2000 in SUR1 remove a critical C-terminal signal required for Bryan J, Aguilar-Bryan L: Sulfonylurea receptors: ABC transporters that regulate ATP-sensitive K channels. Biochim Biophys Acta surface expression. In contrast to the severe hypoglyce1461:285–303, 1999 mia observed in PHHI neonates, Sur1KO mice (like Clement JP IV, Kunjilwar K, Gonzalez G, et al: Association and their KIR6.2KO counterparts) are normoglycemic alstoichiometry of KATP channel subunits. Neuron 18:827–838, 1997 de Rooij J, Zwartkruis FJ, Verheijen MH, et al: Epac is a Rap1 though their -cell electrophysiologic profile is the same guanine-nucleotide-exchange factor directly activated by cyclic as in PHHI: no KATP currents, higher resting membrane AMP. Nature 396:474–477, 1998 potential, spontaneous Ca2 -dependent action potenKawasaki H, Springett GM, Mochizuki N, et al: A family of cAMPbinding proteins that directly activate Rap1. Science 282:2275–2279, tials, and elevated oscillating [Ca2 ]i in low glucose. 1998 These mice are a novel system in which to study KATPKieffer TJ, Habener JF: The glucagon-like peptides. Endocr Rev 20:876–913, 1999 independent regulation of [Ca2 ]i oscillations, insulin se-