title: Neonatal diabetes caused by mutations in sulfonylurea receptor 1: interplay between expression and Mg-nucleotide gating defects of ATP-sensitive potassium channels.
abstract: BACKGROUND
  ATP-sensitive potassium (KATP) channels regulate insulin secretion by coupling glucose metabolism to β-cell membrane potential. Gain-of-function mutations in the sulfonylurea receptor 1 (SUR1) or Kir6.2 channel subunit underlie neonatal diabetes.
  
  
  OBJECTIVE
  The objective of the study was to determine the mechanisms by which two SUR1 mutations, E208K and V324M, associated with transient neonatal diabetes affect KATP channel function.
  
  
  METHODS
  E208K or V324M mutant SUR1 was coexpressed with Kir6.2 in COS cells, and expression and gating properties of the resulting channels were assessed biochemically and electrophysiologically.
  
  
  RESULTS
  Both E208K and V324M augment channel response to MgADP stimulation without altering sensitivity to ATP4- or sulfonylureas. Surprisingly, whereas E208K causes only a small increase in MgADP response consistent with the mild transient diabetes phenotype, V324M causes a severe activating gating defect. Unlike E208K, V324M also impairs channel expression at the cell surface, which is expected to dampen its functional impact on β-cells. When either mutation was combined with a mutation in the second nucleotide binding domain of SUR1 previously shown to abolish Mg-nucleotide response, the activating effect of E208K and V324M was also abolished. Moreover, combination of E208K and V324M results in channels with Mg-nucleotide sensitivity greater than that seen in individual mutations alone.
  
  
  CONCLUSIONS
  The results demonstrate that E208K and V324M, located in distinct domains of SUR1, enhance transduction of Mg-nucleotide stimulation from the SUR1 nucleotide binding folds to Kir6.2. Furthermore, they suggest that diabetes severity is determined by interplay between effects of a mutation on channel expression and channel gating.
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Intza
authors.initials: I
authors.lastname: Garin
authors.forename: Luis
authors.initials: L
authors.lastname: Castaño
authors.forename: Jesús
authors.initials: J
authors.lastname: Argente
authors.forename: Ma Teresa
authors.initials: MT
authors.lastname: Muñoz-Calvo
authors.forename: Guiomar
authors.initials: G
authors.lastname: Perez de Nanclares
authors.forename: Show-Ling
authors.initials: SL
authors.lastname: Shyng
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003920:Diabetes Mellitus / Q000235:genetics*; D005786:Gene Expression Regulation; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000235:genetics*; D054086:KATP Channels / Q000502:physiology*; D008274:Magnesium / Q000502:physiology; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000502:physiology; D011955:Receptors, Drug / Q000235:genetics*; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D054086:KATP Channels; D008274:Magnesium; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human
references.citation: Neuron. 1999 Mar;22(3):537-48
references.pmid: 10197533
references.citation: Nature. 2006 Mar 23;440(7083):470-6
references.pmid: 16554807
references.citation: J Physiol. 1997 Oct 1;504 ( Pt 1):35-45
references.pmid: 9350615
references.citation: J Mol Cell Cardiol. 2005 Jul;39(1):79-98
references.pmid: 15978905
references.citation: EMBO J. 2003 Aug 1;22(15):3833-43
references.pmid: 12881418
references.citation: J Clin Invest. 2000 Oct;106(7):897-906
references.pmid: 11018078
references.citation: Diabetes. 2007 May;56(5):1357-62
references.pmid: 17317760
references.citation: Am J Physiol Endocrinol Metab. 2007 Oct;293(4):E880-9
references.pmid: 17652156
references.citation: J Biol Chem. 2003 Oct 24;278(43):41577-80
references.pmid: 12941953
references.citation: Endocr Rev. 1999 Apr;20(2):101-35
references.pmid: 10204114
references.citation: J Clin Invest. 2008 Aug;118(8):2877-86
references.pmid: 18596924
references.citation: Am J Hum Genet. 2007 Aug;81(2):375-82
references.pmid: 17668386
references.citation: Diabetes. 2007 Jul;56(7):1930-7
references.pmid: 17446535
references.citation: Diabetes. 2007 Jun;56(6):1737-41
references.pmid: 17389331
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2882-7
references.pmid: 11226335
references.citation: J Biol Chem. 2009 Mar 20;284(12):7951-9
references.pmid: 19151370
references.citation: Diabetes. 2005 Sep;54(9):2645-54
references.pmid: 16123353
references.citation: Diabetes. 2007 Sep;56(9):2339-48
references.pmid: 17575084
references.citation: Hum Mutat. 2009 Feb;30(2):170-80
references.pmid: 18767144
references.citation: Diabetes. 2006 Jun;55(6):1738-46
references.pmid: 16731837