Three C-terminal residues from the sulphonylurea receptor contribute to the functional coupling between the KATP channel subunits SUR2A and Kir6.2

Julien P. Dupuis, Jean Revilloud, Christophe J. Moreau, Michel Vivaudou
The Journal of Physiology. 2008-06-28; 586(13): 3075-3085
DOI: 10.1113/jphysiol.2008.152744

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1. J Physiol. 2008 Jul 1;586(13):3075-85. doi: 10.1113/jphysiol.2008.152744. Epub
2008 May 1.

Three C-terminal residues from the sulphonylurea receptor contribute to the
functional coupling between the K(ATP) channel subunits SUR2A and Kir6.2.

Dupuis JP(1), Revilloud J, Moreau CJ, Vivaudou M.

Author information:
(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.

DOI: 10.1113/jphysiol.2008.152744
PMCID: PMC2538783
PMID: 18450778 [Indexed for MEDLINE]

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