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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 586/13/3075    most recent jphysiol.2008.152744v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Dupuis, J. P. Articles by Vivaudou, M. PubMed PubMed Citation Articles by Dupuis, J. P. Articles by Vivaudou, M. Related Collections Molecular and Genomic

¹ Institut de Biologie Structurale, UMR5075 CEA-CNRS-University J. Fourier, 41, rue Jules Horowitz, 38027 Grenoble, France

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.

(Received 18 February 2008; accepted after revision 30 April 2008; first published online 1 May 2008)
Corresponding author M. Vivaudou: IBS/LPM, 41, rue Jules Horowitz, 38027 Grenoble, France. Email: vivaudou{at}cea.fr

This paper has online supplemental material.