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Research ArticleArticle

Coexpression with the Inward Rectifier K+ Channel Kir6.1 Increases the Affinity of the Vascular Sulfonylurea Receptor SUR2B for Glibenclamide

Ulrich Russ, Annette Hambrock, Ferruh Artunc, Cornelia Löffler-Walz, Yoshiyuki Horio, Yoshihisa Kurachi and Ulrich Quast
Molecular Pharmacology November 1999, 56 (5) 955-961; DOI: https://doi.org/10.1124/mol.56.5.955
Ulrich Russ
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Annette Hambrock
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Ferruh Artunc
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Cornelia Löffler-Walz
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Yoshiyuki Horio
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Yoshihisa Kurachi
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Ulrich Quast
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Abstract

ATP-sensitive K+ channels are closed by the hypoglycemic sulfonylureas like glibenclamide (GBC) and activated by a class of vasorelaxant compounds, the K+ channel openers. These channels are octamers of Kir6.x and sulfonylurea receptor (SUR) subunits with 4:4 stoichiometry. The properties of the opener-sensitive K+ channel in the vasculature are well matched by the SUR2B/Kir6.1 channel; however, the GBC sensitivity of the recombinant channel is unknown. In binding experiments we have determined the affinity of GBC for SUR2B and the SUR2B/Kir6.1 channel and compared the results with the channel blocking potency of GBC. All experiments were performed in whole transfected human embryonic kidney cells at 37°C. The equilibrium dissociation constants (K D) of GBC binding to SUR2B and to the SUR2B/Kir6.1 complex were determined to be 32 and 6 nM, respectively; the K D value of the opener P1075 (N-cyano-N′-(1,1-dimethylpropyl)-N′′-3-pyridylguanidine) (≈5 nM) was, however, not affected by cotransfection. In whole cell voltage-clamp experiments, GBC inhibited the SUR2B/Kir6.1 channel with IC50 ≈ 43 nM. The data show that, in the intact cell: 1) SUR2B, previously considered to be a low-affinity SUR, has a rather high affinity for GBC; 2) coexpression with the inward rectifier Kir6.1 increases the affinity of SUR2B for GBC; 3) the recombinant channel exhibits the same GBC affinity as the opener-sensitive K+ channel in vascular tissue; and 4) theK D value of GBC binding to the octameric channel is 7 times lower than the IC50 value for channel inhibition. The latter finding suggests that occupation of all four GBC sites per channel is required for channel closure.

Footnotes

    • Received March 24, 1999.
    • Accepted August 9, 1999.
  • Send reprint requests to: Dr. Ulrich Quast, Dept. of Pharmacology, University of Tübingen, Wilhemstr. 56, D-72074 Tübingen, Germany. E-mail: ulrich.quast{at}uni-tuebingen.de

  • This study was supported by the Deutsche Forschungsgemeinschaft (Qu 100/2–2, U.Q. and U.R.) and by a grant from the Federal Ministry of Education, Science, Research and Technology, and the Interdisciplinary Center for Clinical Research (IZKF) Tübingen Fö.(01KS 9602, F.A.).

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Molecular Pharmacology: 56 (5)
Molecular Pharmacology
Vol. 56, Issue 5
1 Nov 1999
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Research ArticleArticle

Coexpression with the Inward Rectifier K+ Channel Kir6.1 Increases the Affinity of the Vascular Sulfonylurea Receptor SUR2B for Glibenclamide

Ulrich Russ, Annette Hambrock, Ferruh Artunc, Cornelia Löffler-Walz, Yoshiyuki Horio, Yoshihisa Kurachi and Ulrich Quast
Molecular Pharmacology November 1, 1999, 56 (5) 955-961; DOI: https://doi.org/10.1124/mol.56.5.955

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Research ArticleArticle

Coexpression with the Inward Rectifier K+ Channel Kir6.1 Increases the Affinity of the Vascular Sulfonylurea Receptor SUR2B for Glibenclamide

Ulrich Russ, Annette Hambrock, Ferruh Artunc, Cornelia Löffler-Walz, Yoshiyuki Horio, Yoshihisa Kurachi and Ulrich Quast
Molecular Pharmacology November 1, 1999, 56 (5) 955-961; DOI: https://doi.org/10.1124/mol.56.5.955
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