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Vol. 56, Issue 5, 955-961, November 1999

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

Department of Pharmacology, University of Tuebingen, Tuebingen, Germany (U.R., A.H., F.A., C.L.-W., U.Q.); and Department of Pharmacology II, Faculty of Medicine, Osaka University, Osaka, Japan (Y.H., Y.K.)

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 (KD) of GBC binding to SUR2B and to the SUR2B/Kir6.1 complex were determined to be 32 and 6 nM, respectively; the KD value of the opener P1075 (N-cyano-N'-(1,1-dimethylpropyl)-N''-3-pyridylguanidine) (approx 5 nM) was, however, not affected by cotransfection. In whole cell voltage-clamp experiments, GBC inhibited the SUR2B/Kir6.1 channel with IC50 approx  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) the KD 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.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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