Document Detail

Neonatal diabetes caused by mutations in sulfonylurea receptor 1: interplay between expression and Mg-nucleotide gating defects of ATP-sensitive potassium channels.
MedLine Citation:
PMID:  20810569     Owner:  NLM     Status:  MEDLINE    
CONTEXT: 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.
DESIGN: 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.
CONCLUSION: 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.
Qing Zhou; Intza Garin; Luis Castaño; Jesús Argente; Ma Teresa Muñoz-Calvo; Guiomar Perez de Nanclares; Show-Ling Shyng
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-09-01
Journal Detail:
Title:  The Journal of clinical endocrinology and metabolism     Volume:  95     ISSN:  1945-7197     ISO Abbreviation:  J. Clin. Endocrinol. Metab.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-06     Completed Date:  2011-01-14     Revised Date:  2013-02-26    
Medline Journal Info:
Nlm Unique ID:  0375362     Medline TA:  J Clin Endocrinol Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  E473-8     Citation Subset:  AIM; IM    
Department of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239, USA.
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MeSH Terms
ATP-Binding Cassette Transporters / genetics*
Amino Acid Substitution
COS Cells
Cercopithecus aethiops
Diabetes Mellitus / genetics*
Gene Expression Regulation
Infant, Newborn
Infant, Newborn, Diseases / genetics*
KATP Channels / physiology*
Magnesium / physiology
Potassium Channels, Inwardly Rectifying / genetics*,  physiology
Receptors, Drug / genetics*
Grant Support
Reg. No./Substance:
0/KATP Channels; 0/Kir6.2 channel; 0/Potassium Channels, Inwardly Rectifying; 0/Receptors, Drug; 0/sulfonylurea receptor; 7439-95-4/Magnesium

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