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ENDOCRINE AND DIABETES

Testing the Bipartite Model of the Sulfonylurea Receptor Binding Site: Binding of A-, B-, and A + B-Site Ligands

Department of Pharmacology and Toxicology, Medical Faculty, University of Tübingen, Tübingen, Germany

ATP-sensitive K⁺ (K_ATP) channels are composed of pore-forming subunits (Kir6.x) and of regulatory subunits, the sulfonylurea receptors (SURx). Subtypes of K_ATP channels are expressed in different organs. The sulfonylureas and glinides (insulinotropes) close the K_ATP channel in pancreatic -cells and stimulate insulin secretion. The insulinotrope binding site of the pancreatic channel (Kir6.2/SUR1) consists of two overlapping (sub)-sites, site A, located on SUR1 and containing Ser1237 (which in SUR2 is replaced by Tyr1206), and site B, formed by SUR1 and Kir6.2. Insulinotropes bind to the A-, B-, or A + B-site(s) and are grouped accordingly. A-ligands are highly selective in closing the pancreatic channel, whereas B-ligands are nonselective and insensitive to the mutation S1237Y. We have examined the binding of insulinotropes representative of the three groups in [³H]glibenclamide competition experiments to determine the contribution of Kir6.x to binding affinity, the effect of the mutation Y1206S in site A of SUR2, and the subtype selectivity of the compounds. The results show that the bipartite nature of the SUR1 binding site applies also to SUR2. Kir6.2 as part of the B-site may interact directly or allosterically with structural elements common to all insulinotropes, i.e., the negative charge and/or the adjacent phenyl ring. The B-site confers a moderate subtype selectivity on B-ligands. The affinity of B-ligands is altered by the mutation SUR2(Y1206S), suggesting that the mutation affects the binding chamber of SUR2 as a whole or subsite A, including the region where the subsites overlap.

Address correspondence to: Dr. Ulrich Quast, Department of Pharmacology and Toxicology, Medical Faculty, University of Tübingen, Wilhelmstrasse 56, D-72074 Tübingen, Germany. E-mail: ulrich.quast{at}uni-tuebingen.de

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				M. Winkler, R. Lutz, U. Russ, U. Quast, and J. Bryan Analysis of Two KCNJ11 Neonatal Diabetes Mutations, V59G and V59A, and the Analogous KCNJ8 I60G Substitution: DIFFERENCES BETWEEN THE CHANNEL SUBTYPES FORMED WITH SUR1 J. Biol. Chem., March 13, 2009; 284(11): 6752 - 6762. [Abstract] [Full Text] [PDF]