title: Functional analysis of two Kir6.2 (KCNJ11) mutations, K170T and E322K, causing neonatal diabetes.
abstract: Heterozygous activating mutations in Kir6.2 (KCNJ11), the pore-forming subunit of the adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channel, are a common cause of neonatal diabetes (ND). We assessed the functional effects of two Kir6.2 mutations associated with ND: K170T and E322K. K(ATP) channels were expressed in Xenopus oocytes, and the heterozygous state was simulated by coexpression of wild-type and mutant Kir6.2 with SUR1 (the beta cell type of sulphonylurea receptor (SUR)). Both mutations reduced the sensitivity of the K(ATP) channel to inhibition by MgATP and enhanced whole-cell K(ATP) currents. In pancreatic beta cells, such an increase in the K(ATP) current is expected to reduce insulin secretion and thereby cause diabetes. The E322K mutation was without effect when Kir6.2 was expressed in the absence of SUR1, suggesting that this residue impairs coupling to SUR1. This is consistent with its predicted location on the outer surface of the tetrameric Kir6.2 pore. The kinetics of K170T channel opening and closing were altered by the mutation, which may contribute to the lower ATP sensitivity. Neither mutation affected the sensitivity of the channel to inhibition by the sulphonylurea tolbutamide, suggesting that patients carrying these mutations may respond to these drugs.
authors.affiliation: University Laboratory of Physiology, Oxford University, Oxford, UK.
authors.forename: A I
authors.initials: AI
authors.lastname: Tarasov
authors.forename: C A
authors.initials: CA
authors.lastname: Girard
authors.forename: B
authors.initials: B
authors.lastname: Larkin
authors.forename: P
authors.initials: P
authors.lastname: Tammaro
authors.forename: S E
authors.initials: SE
authors.lastname: Flanagan
authors.forename: S
authors.initials: S
authors.lastname: Ellard
authors.forename: F M
authors.initials: FM
authors.lastname: Ashcroft
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology; D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics* / Q000503:physiopathology; D004553:Electric Conductivity; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D009154:Mutation / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051381:Rats; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel