title: Identification of a familial hyperinsulinism-causing mutation in the sulfonylurea receptor 1 that prevents normal trafficking and function of KATP channels.
abstract: Mutations in the pancreatic ATP-sensitive potassium (K(ATP)) channel subunits sulfonylurea receptor 1 (SUR1) and the inwardly rectifying potassium channel Kir6.2 cause persistent hyperinsulinemic hypoglycemia of infancy. We have identified a SUR1 mutation, L1544P, in a patient with the disease. Channels formed by co-transfection of Kir6.2 and the mutant SUR1 in COS cells have reduced response to MgADP ( approximately 10% that of the wild-type channels) and reduced surface expression ( approximately 19% that of the wild-type channels). However, the steady-state level of the SUR1 protein is unaffected. Treating cells with lysosomal or proteasomal inhibitors did not improve surface expression of the mutant channels, suggesting that increased degradation of mutant channels by either pathway is unlikely to account for the reduced surface expression. Removal of the RKR endoplasmic reticulum retention/retrieval trafficking motif in either SUR1 or Kir6.2 increased the surface expression of the mutant channel by approximately 35 and approximately 20%, respectively. The simultaneous removal of the RKR motif in both channel subunits restored surface expression of the mutant channel to the wild-type channel levels. Thus, the L1544P mutation may interfere with normal trafficking of K(ATP) channels by causing improper shielding of the RKR endoplasmic reticulum retention/retrieval trafficking signals in the two channel subunits.
authors.affiliation: Center for Research on Occupational and Environmental Toxicology, the Department of Medicine, Oregon Health and Science University, Portland, Oregon 97201, USA.
authors.forename: Grit
authors.initials: G
authors.lastname: Taschenberger
authors.forename: Adam
authors.initials: A
authors.lastname: Mougey
authors.forename: Shu
authors.initials: S
authors.lastname: Shen
authors.forename: Linda B
authors.initials: LB
authors.lastname: Lester
authors.forename: Stephen
authors.initials: S
authors.lastname: LaFranchi
authors.forename: Show-Ling
authors.initials: SL
authors.lastname: Shyng
mesh_terms: D018528:ATP-Binding Cassette Transporters; D020816:Amino Acid Motifs; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001483:Base Sequence; D015153:Blotting, Western; D019556:COS Cells; D006224:Cricetinae; D018076:DNA, Complementary / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D015151:Immunoblotting; D008163:Luminescent Measurements; D008247:Lysosomes / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D018408:Patch-Clamp Techniques; D010957:Plasmids / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011955:Receptors, Drug / Q000235:genetics*; D012413:Rubidium / Q000494:pharmacology; D015398:Signal Transduction; D064233:Sulfonylurea Receptors; D013997:Time Factors; D014162:Transfection
chemical_list: C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D000959:Antihypertensive Agents; D018076:DNA, Complementary; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D012413:Rubidium; D003981:Diazoxide; D005905:Glyburide