| Three C-terminal residues from the sulphonylurea receptor contribute to the functional coupling between the K(ATP) channel subunits SUR2A and Kir6.2. | |
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MedLine Citation:
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PMID: 18450778 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Cardiac ATP-sensitive potassium (K(ATP)) channels are metabolic sensors formed by the association of the inward rectifier potassium channel Kir6.2 and the sulphonylurea receptor SUR2A. SUR2A adjusts channel gating as a function of intracellular ATP and ADP and is the target of pharmaceutical openers and blockers which, respectively, up- and down-regulate Kir6.2. In an effort to understand how effector binding to SUR2A translates into Kir6.2 gating modulation, we examined the role of a 65-residue SUR2A fragment linking transmembrane domain TMD2 and nucleotide-binding domain NBD2 that has been shown to interact with Kir6.2. This fragment of SUR2A was replaced by the equivalent residues of its close homologue, the multidrug resistance protein MRP1. The chimeric construct was expressed in Xenopus oocytes and characterized using the patch-clamp technique. We found that activation by MgADP and synthetic openers was greatly attenuated although apparent affinities were unchanged. Further chimeragenetic and mutagenetic studies showed that mutation of three residues, E1305, I1310 and L1313 (rat numbering), was sufficient to confer this defective phenotype. The same mutations had no effects on channel block by the sulphonylurea glibenclamide or by ATP, suggesting a role for these residues in activatory--but not inhibitory--transduction processes. These results indicate that, within the K(ATP) channel complex, the proximal C-terminal of SUR2A is a critical link between ligand binding to SUR2A and Kir6.2 up-regulation. |
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Authors:
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Julien P Dupuis; Jean Revilloud; Christophe J Moreau; Michel Vivaudou |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-05-01 |
Journal Detail:
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Title: The Journal of physiology Volume: 586 ISSN: 1469-7793 ISO Abbreviation: J. Physiol. (Lond.) Publication Date: 2008 Jul |
Date Detail:
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Created Date: 2008-07-02 Completed Date: 2008-11-13 Revised Date: 2013-06-05 |
Medline Journal Info:
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Nlm Unique ID: 0266262 Medline TA: J Physiol Country: England |
Other Details:
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Languages: eng Pagination: 3075-85 Citation Subset: IM |
Affiliation:
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Institut de Biologie Structurale, UMR5075 CEA-CNRS-University J. Fourier, 41, rue Jules Horowitz, 38027 Grenoble, France. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
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chemistry,
genetics,
metabolism* Animals Gene Expression Regulation Guanidines / pharmacology Humans Ion Channel Gating / physiology Ligands Mice Multidrug Resistance-Associated Proteins / chemistry, genetics, metabolism* Mutation Oocytes Potassium Channels / chemistry, metabolism* Potassium Channels, Inwardly Rectifying / chemistry, genetics, metabolism* Protein Binding Pyridines / pharmacology Rats Receptors, Drug / chemistry, genetics, metabolism* Xenopus |
| Chemical | |
Reg. No./Substance:
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0/Guanidines; 0/Kir6.2 channel; 0/Ligands; 0/Multidrug Resistance-Associated Proteins; 0/Potassium Channels; 0/Potassium Channels, Inwardly Rectifying; 0/Pyridines; 0/Receptors, Drug; 0/mitochondrial K(ATP) channel; 0/multidrug resistance-associated protein 1; 0/sulfonylurea receptor; 60559-98-0/N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine |
| Comments/Corrections | |
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