title: Pharmacological Correction of Trafficking Defects in ATP-sensitive Potassium Channels Caused by Sulfonylurea Receptor 1 Mutations.
abstract: ATP-sensitive potassium (KATP) channels play a key role in mediating glucose-stimulated insulin secretion by coupling metabolic signals to β-cell membrane potential. Loss of KATPchannel function due to mutations in ABCC8 or KCNJ11, genes encoding the sulfonylurea receptor 1 (SUR1) or the inwardly rectifying potassium channel Kir6.2, respectively, results in congenital hyperinsulinism. Many SUR1 mutations prevent trafficking of channel proteins from the endoplasmic reticulum to the cell surface. Channel inhibitors, including sulfonylureas and carbamazepine, have been shown to correct channel trafficking defects. In the present study, we identified 13 novel SUR1 mutations that cause channel trafficking defects, the majority of which are amenable to pharmacological rescue by glibenclamide and carbamazepine. By contrast, none of the mutant channels were rescued by KATPchannel openers. Cross-linking experiments showed that KATPchannel inhibitors promoted interactions between the N terminus of Kir6.2 and SUR1, whereas channel openers did not, suggesting the inhibitors enhance intersubunit interactions to overcome channel biogenesis and trafficking defects. Functional studies of rescued mutant channels indicate that most mutants rescued to the cell surface exhibited WT-like sensitivity to ATP, MgADP, and diazoxide. In intact cells, recovery of channel function upon trafficking rescue by reversible sulfonylureas or carbamazepine was facilitated by the KATPchannel opener diazoxide. Our study expands the list of KATPchannel trafficking mutations whose function can be recovered by pharmacological ligands and provides further insight into the structural mechanism by which channel inhibitors correct channel biogenesis and trafficking defects.
authors: From the Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239.
authors: Gregory M
authors: GM
authors: Martin
authors: From the Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239.
authors: Emily A
authors: EA
authors: Rex
authors: From the Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239.
authors: Prasanna
authors: P
authors: Devaraneni
authors: the Department of Anesthesiology, Vanderbilt University, Nashville, Tennessee 37232, and.
authors: Jerod S
authors: JS
authors: Denton
authors: the Division of Endocrinology/Diabetes, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
authors: Kara E
authors: KE
authors: Boodhansingh
authors: the Division of Endocrinology/Diabetes, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
authors: Diva D
authors: DD
authors: DeLeon
authors: the Division of Endocrinology/Diabetes, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
authors: Charles A
authors: CA
authors: Stanley
authors: From the Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239, shyngs@ohsu.edu.
authors: Show-Ling
authors: SL
authors: Shyng
mesh_terms: D002220:Carbamazepine / Q000494:pharmacology*; D005260:Female; D005905:Glyburide / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D064233:Sulfonylurea Receptors / Q000235:genetics / Q000378:metabolism*; D000099161:Kcnj11 Channel
chemical_list: D002220:Carbamazepine; D005905:Glyburide; D024661:Potassium Channels, Inwardly Rectifying; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human
keywords: ABC transporter; ATP-binding cassette transporter subfamily C member 8 (ABCC8); chaperone; gating; hypoglycemia; insulin secretion; intracellular trafficking; potassium channel; protein misfolding; protein processing