title: Carbamazepine as a novel small molecule corrector of trafficking-impaired ATP-sensitive potassium channels identified in congenital hyperinsulinism.
abstract: ATP-sensitive potassium (KATP) channels consisting of sulfonylurea receptor 1 (SUR1) and the potassium channel Kir6.2 play a key role in insulin secretion by coupling metabolic signals to β-cell membrane potential. Mutations in SUR1 and Kir6.2 that impair channel trafficking to the cell surface lead to loss of channel function and congenital hyperinsulinism. We report that carbamazepine, an anticonvulsant, corrects the trafficking defects of mutant KATP channels previously identified in congenital hyperinsulinism. Strikingly, of the 19 SUR1 mutations examined, only those located in the first transmembrane domain of SUR1 responded to the drug. We show that unlike that reported for several other protein misfolding diseases, carbamazepine did not correct KATP channel trafficking defects by activating autophagy; rather, it directly improved the biogenesis efficiency of mutant channels along the secretory pathway. In addition to its effect on channel trafficking, carbamazepine also inhibited KATP channel activity. Upon subsequent removal of carbamazepine, however, the function of rescued channels was recovered. Importantly, combination of the KATP channel opener diazoxide and carbamazepine led to enhanced mutant channel function without carbamazepine washout. The corrector effect of carbamazepine on mutant KATP channels was also demonstrated in rat and human β-cells with an accompanying increase in channel activity. Our findings identify carbamazepine as a novel small molecule corrector that may be used to restore KATP channel expression and function in a subset of congenital hyperinsulinism patients.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239 and.
authors.forename: Pei-Chun
authors.initials: PC
authors.lastname: Chen
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239 and.
authors.forename: Erik M
authors.initials: EM
authors.lastname: Olson
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239 and.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239 and.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Kryukova
authors.affiliation: Department of Biochemistry, McGill University, Montréal, Québec H3G 1Y6, Canada.
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Sampson
authors.affiliation: Department of Biochemistry, McGill University, Montréal, Québec H3G 1Y6, Canada.
authors.forename: David Y
authors.initials: DY
authors.lastname: Thomas
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239 and. Electronic address: shyngs@ohsu.edu.
authors.forename: Show-Ling
authors.initials: SL
authors.lastname: Shyng
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D019556:COS Cells; D002220:Carbamazepine / Q000737:chemistry / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D044903:Congenital Hyperinsulinism / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007340:Insulinoma / Q000378:metabolism / Q000473:pathology; D015640:Ion Channel Gating / Q000187:drug effects; D054086:KATP Channels / Q000378:metabolism*; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D064233:Sulfonylurea Receptors / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors
chemical_list: D054086:KATP Channels; D050505:Mutant Proteins; D054852:Small Molecule Libraries; D064233:Sulfonylurea Receptors; D002220:Carbamazepine
keywords: ABC Transporter; CFTR; Carbamazepine; Hyperinsulinism; Intracellular Trafficking; KATP Channel; Molecular Chaperone; Potassium Channels; Sulfonylurea Receptor 1; β-Cells