Sulfonylureas correct trafficking defects of disease-causing ATP-sensitive potassium channels by binding to the channel complex.
ATP-sensitive potassium (K(ATP)) channels mediate glucose-induced insulin secretion by coupling metabolic signals to beta-cell membrane potential and the secretory machinery. Reduced K(ATP) channel expression caused by mutations in the channel proteins: sulfonylurea receptor 1 (SUR1) and Kir6.2, results in loss of channel function as seen in congenital hyperinsulinism. Previously, we reported that sulfonylureas, oral hypoglycemic drugs widely used to treat type II diabetes, correct the endoplasmic reticulum to the plasma membrane trafficking defect caused by two SUR1 mutations, A116P and V187D. In this study, we investigated the mechanism by which sulfonylureas rescue these mutants. We found that glinides, another class of SUR-binding hypoglycemic drugs, also markedly increased surface expression of the trafficking mutants. Attenuating or abolishing the ability of mutant SUR1 to bind sulfonylureas or glinides by the following mutations: Y230A, S1238Y, or both, accordingly diminished the rescuing effects of the drugs. Interestingly, rescue of the trafficking defects requires mutant SUR1 to be co-expressed with Kir6.2, suggesting that the channel complex, rather than SUR1 alone, is the drug target. Observations that sulfonylureas also reverse trafficking defects caused by neonatal diabetes-associated Kir6.2 mutations in a way that is dependent on intact sulfonylurea binding sites in SUR1 further support this notion. Our results provide insight into the mechanistic and structural basis on which sulfonylureas rescue K(ATP) channel surface expression defects caused by channel mutations.
Yan
Fei-Fei
FF
Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, Oregon 97239, USA.
Casey
Jillene
J
Shyng
Show-Ling
SL
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000596:Amino Acids / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004194:Disease; D004594:Electrophysiology; D015870:Gene Expression; D009154:Mutation / Q000235:genetics; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D012680:Sensitivity and Specificity; D013453:Sulfonylurea Compounds / Q000737:chemistry / Q000378:metabolism*
D000596:Amino Acids; D015221:Potassium Channels; D021122:Protein Subunits; D013453:Sulfonylurea Compounds; D000255:Adenosine Triphosphate