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Role of the amino-terminal transmembrane domain of sulfonylurea receptor SUR2B for coupling to KIR6.2, ligand binding, and oligomerization

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Abstract

ATP-sensitive K+ (KATP) channels consist of two types of subunits, KIR6.x that form the pore, and sulfonylurea receptors (SURs) that serve as regulatory subunits. SURs are ATP-binding cassette (ABC) proteins and contain, in addition to two nucleotide binding folds, the binding sites for channel openers such as diazoxide and P1075 and channel inhibitors such as glibenclamide (GBC) and repaglinide. Structurally, SURs differ from most eukaryotic ABC proteins by an additional amino-terminal transmembrane domain (TMD0); in case of SUR1, the subunit of the pancreatic KATP channel, TMD0 serves as a major domain for association with KIR. In this study we sought to elucidate the roles of TMD0 in SUR2B, the smooth muscle gating subunit, in the coupling between SUR2B and KIR6.2, in the self-association of SUR2B and in channel modulator binding to SUR2B. SUR2B has a weaker affinity for sulfonylureas thus SUR2BY1206S, with a higher affinity for GBC, but an equivalent opener binding was used. Association of SUR2BYSΔ, lacking TMD0, with KIR6.2 was shown by immunoprecipitation; however, no evidence for formation of functional channels was obtained. SUR2BYSΔ self-associates like SUR2BYS and binds GBC, repaglinide, and P1075 with slightly reduced affinities. The binding profile of the SUR2BYSΔ/KIR6.2 complex differs slightly but significantly from that of SUR2BYSΔ alone showing impaired allosteric coupling of binding sites. We conclude that TMD0 is not required for oligomerization of SUR2B, is of only minor importance in ligand binding, but is essential for both functional and allosteric coupling of SUR2B to KIR6.2.

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Abbreviations

GBC:

Glibenclamide

IP:

Immunoprecipitation

KATP :

ATP-sensitive K+ channels

KIR :

Inwardly rectifying K+ channel

NBF:

Nucleotide binding fold

P1075:

N-cyano-N′-(1,1-dimethylpropyl)-N″-3-pyridylguanidine

SUR:

Sulfonylurea receptor

TMD0:

Transmembrane domain 0

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Acknowledgments

The authors would like to thank Profs. Y. Kurachi and Y. Horio (Osaka, Japan) for the murine clone of SUR2B. This work was supported by the Deutsche Forschungsgemeinschaft grant Qu100/4-1 (UQ), the Dr. Karl Kuhn-Stiftung (UR), and ADA Grant 1-10-BS21 (JB).

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  1. Marcus Winkler

    Present address: Department of Laboratory Medicine, Lund Stem Cell Center, Lund University, Klinikgatan 26, 22184, Lund, Sweden

Authors and Affiliations

  1. Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard-Karls-University Hospitals and Clinics, Wilhelmstr. 56, 72074, Tübingen, Germany

    Marcus Winkler, Petra Kühner, Ulrich Russ & Ulrich Quast

  2. Pacific Northwest Diabetes Research Institute, 720 Broadway, Seattle, WA, 98122, USA

    David Ortiz & Joseph Bryan

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  1. Marcus Winkler
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Correspondence to Ulrich Quast.

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Winkler, M., Kühner, P., Russ, U. et al. Role of the amino-terminal transmembrane domain of sulfonylurea receptor SUR2B for coupling to KIR6.2, ligand binding, and oligomerization. Naunyn-Schmiedeberg's Arch Pharmacol 385, 287–298 (2012). https://doi.org/10.1007/s00210-011-0708-9

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