title: Modulation of the trafficking efficiency and functional properties of ATP-sensitive potassium channels through a single amino acid in the sulfonylurea receptor.
abstract: Mutations in the sulfonylurea receptor 1 (SUR1), a subunit of ATP-sensitive potassium (K(ATP)) channels, cause familial hyperinsulinism. One such mutation, deletion of phenylalanine 1388 (DeltaPhe-1388), leads to defects in both trafficking and MgADP response of K(ATP) channels. Here we investigated the biochemical features of Phe-1388 that control the proper trafficking and function of K(ATP) channels by substituting the residue with all other 19 amino acids. Whereas surface expression is largely dependent on hydrophobicity, channel response to MgADP is governed by multiple factors and involves the detailed architecture of the amino acid side chain. Thus, structural features in SUR1 required for proper channel function are distinct from those required for correct protein trafficking. Remarkably, replacing Phe-1388 by leucine profoundly alters the physiological and pharmacological properties of the channel. The F1388L-SUR1 channel has increased sensitivity to MgADP and metabolic inhibition, decreased sensitivity to glibenclamide, and responds to both diazoxide and pinacidil. Because this conservative amino acid substitution occurs in the SUR2A and SUR2B isoforms, the mutation provides a mechanism by which functional diversities in K(ATP) channels are generated.
authors.affiliation: Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, Oregon 97201, USA.
authors.forename: Etienne A
authors.initials: EA
authors.lastname: Cartier
authors.forename: Shu
authors.initials: S
authors.lastname: Shen
authors.forename: Show-Ling
authors.initials: SL
authors.lastname: Shyng
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D015153:Blotting, Western; D019556:COS Cells; D006224:Cricetinae; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology; D015151:Immunoblotting; D008163:Luminescent Measurements; D008274:Magnesium / Q000378:metabolism; D051379:Mice; D009154:Mutation; D018408:Patch-Clamp Techniques; D020110:Pinacidil / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000378:metabolism; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051381:Rats; D011955:Receptors, Drug / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012413:Rubidium / Q000494:pharmacology; D064233:Sulfonylurea Receptors; D013997:Time Factors; D014162:Transfection; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; C577508:Abcc8 protein, mouse; C577509:Abcc8 protein, rat; C577511:Abcc9 protein, mouse; D000889:Anti-Arrhythmia Agents; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D020033:Protein Isoforms; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D014665:Vasodilator Agents; D000244:Adenosine Diphosphate; D020110:Pinacidil; D000255:Adenosine Triphosphate; D008274:Magnesium; D012413:Rubidium; D003981:Diazoxide; D011188:Potassium; D005905:Glyburide