| Neonatal diabetes caused by mutations in sulfonylurea receptor 1: interplay between expression and Mg-nucleotide gating defects of ATP-sensitive potassium channels. | |
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MedLine Citation:
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PMID: 20810569 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-09-01 |
Journal Detail:
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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:
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Created Date: 2010-12-06 Completed Date: 2011-01-14 Revised Date: 2013-02-26 |
Medline Journal Info:
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Nlm Unique ID: 0375362 Medline TA: J Clin Endocrinol Metab Country: United States |
Other Details:
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Languages: eng Pagination: E473-8 Citation Subset: AIM; IM |
Affiliation:
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Department of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
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genetics* Amino Acid Substitution Animals COS Cells Cercopithecus aethiops Diabetes Mellitus / genetics* Gene Expression Regulation Heterozygote Humans Infant, Newborn Infant, Newborn, Diseases / genetics* KATP Channels / physiology* Magnesium / physiology Mutation Potassium Channels, Inwardly Rectifying / genetics*, physiology Receptors, Drug / genetics* |
| Grant Support | |
ID/Acronym/Agency:
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DK66485/DK/NIDDK NIH HHS; R01DK57699/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/KATP Channels; 0/Kir6.2 channel; 0/Potassium Channels, Inwardly Rectifying; 0/Receptors, Drug; 0/sulfonylurea receptor; 7439-95-4/Magnesium |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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