The Journal of General Physiology
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Published online
doi:10.1085/jgp.200709852
The Journal of General Physiology, Vol. 131, No. 3, 185-196
The Rockefeller University Press, 0022-1295 $30.00
© Karger et al.
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ARTICLE

 Role for SUR2A ED Domain in Allosteric Coupling within the KATP Channel Complex



Amy B. Karger, Sungjo Park, Santiago Reyes, Martin Bienengraeber, Roy B. Dyer, Andre Terzic, and Alexey E. Alekseev

Division of Cardiovascular Diseases, Department of Medicine and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905

Correspondence to Alexey E. Alekseev: aea03{at}mayo.edu

Allosteric regulation of heteromultimeric ATP-sensitive potassium (KATP) channels is unique among protein systems as it implies transmission of ligand-induced structural adaptation at the regulatory SUR subunit, a member of ATP-binding cassette ABCC family, to the distinct pore-forming K+ (Kir6.x) channel module. Cooperative interaction between nucleotide binding domains (NBDs) of SUR is a prerequisite for KATP channel gating, yet pathways of allosteric intersubunit communication remain uncertain. Here, we analyzed the role of the ED domain, a stretch of 15 negatively charged aspartate/glutamate amino acid residues (948–962) of the SUR2A isoform, in the regulation of cardiac KATP channels. Disruption of the ED domain impeded cooperative NBDs interaction and interrupted the regulation of KATP channel complexes by MgADP, potassium channel openers, and sulfonylurea drugs. Thus, the ED domain is a structural component of the allosteric pathway within the KATP channel complex integrating transduction of diverse nucleotide-dependent states in the regulatory SUR subunit to the open/closed states of the K+-conducting channel pore.

Abbreviations used in this paper: ABC, ATP-binding cassette; CL, cytoplasmic loop; HRP, horseradish peroxidase; KCO, potassium channel opener; NBD, nucleotide binding domain; SUR, sulfonylurea receptor; TMD, transmembrane-spanning domain.


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