Interaction of K<sub>ATP</sub>Channel Modulators with Sulfonylurea Receptor SUR2B: Implication for Tetramer Formation and Allosteric Coupling of Subunits

Löffler-Walz, Cornelia; Hambrock, Annette; Quast, Ulrich

doi:10.1124/mol.61.2.407

Cited by 26 publications

(45 citation statements)

References 36 publications

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“…This is in contrast to data from Schwanstecher et al (23), suggesting complete displacement of [ 3 H]glibenclamide by pinacidil and diazoxide at SUR1, but is in accordance with previous results showing displacement only to ϳ80% (l-pinacidil) and ϳ50% (diazoxide) at SUR1 or the splice variant SUR1⌬17 (20). This suggests the existence of SUR1 complexes in which glibenclamide and openers are bound simultaneously (8).…”

Section: Discussionsupporting

confidence: 86%

“…In addition, the increase in [ 3 H]glibenclamide binding seen with wild-type SUR1, indicating additional positive allosteric interactions at lower concentrations of these openers at SUR1, is missing at SUR1(T1285L, M1289T). One could speculate that the observed allosteric effects are due to molecular interactions within the SUR monomer or even between subunits of the SUR tetramer as already proposed for allosteric coupling between nucleotide, opener, and sulfonylurea binding to tetrameric SUR2 (8). According to such an assumption, the nature of allosteric coupling at SUR1 could be profoundly influenced by mutation in TM17.…”

Section: Discussionmentioning

confidence: 67%

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Effect of Two Amino Acids in TM17 of Sulfonylurea Receptor SUR1 on the Binding of ATP-Sensitive K+ Channel Modulators

et al. 2004

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The sulfonylurea receptor (SUR) is the important regulatory subunit of ATP-sensitive K ؉ channels. It is an ATP-binding cassette protein comprising 17 transmembrane helices. SUR is endowed with binding sites for channel blockers like the antidiabetic sulfonylurea glibenclamide and for the chemically very heterogeneous channel openers. SUR1, the typical pancreatic SUR isoform, shows much higher affinity for glibenclamide but considerably lower affinity for most openers than SUR2. In radioligand binding assays, we investigated the role of two amino acids, T1285 and M1289, located in transmembrane helix (TM)-17, in opener binding to SUR1. These amino acids were exchanged for the corresponding amino acids of SUR2. In competition experiments using [ 3 H]glibenclamide as radioligand, SUR1(T1285L, M1289T) showed much higher affinity toward the cyanoguanidine openers pinacidil and P1075 than SUR1 wild type. The affinity for the thioformamide aprikalim was also markedly increased. In contrast, the affinity for the benzopyrans rilmakalim and levcromakalim was unaffected; however, the amount of displaced [ 3 H] glibenclamide binding was nearly doubled. The binding properties of the opener diazoxide and the blocker glibenclamide were unchanged. In conclusion, mutation of two amino acids in TM17 of SUR1, especially of M1289, leads to class-specific effects on opener binding by increasing opener affinity or by changing allosteric coupling between opener and glibenclamide binding. Diabetes 53 (Suppl. 3)

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 67%

Effect of Two Amino Acids in TM17 of Sulfonylurea Receptor SUR1 on the Binding of ATP-Sensitive K+ Channel Modulators

et al. 2004

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“…Both methods gave identical results (see e.g., Russ et al, 1999;Hambrock et al, 2001;Löffler-Walz et al, 2002). Nonspecific binding ranged from 40 to 60% of total binding (SUR2); in the case of SUR1, nonspecific binding was determined in the presence of 100 nM glibenclamide and was approximately 10%.…”

Section: Materials [mentioning

confidence: 92%

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

Winkler¹,

Stephan²,

Bieger³

et al. 2007

J Pharmacol Exp Ther

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ATP-sensitive K ϩ (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 ϩ 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 [ 3 H]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.Sulfonylureas and glinides (termed here insulinotropes) are used in the therapy of type 2 diabetes. They act by closing the ATP-sensitive K ϩ (K ATP ) channel in pancreatic ␤-cells, thereby inducing depolarization, Ca 2ϩ entry, and insulin secretion (Sturgess et al., 1985; for review, see Proks et al., 2002). K ATP channels are closed by intracellular ATP and opened by MgADP. They are composed of two types of subunits, inwardly rectifying K ϩ channels (Kir6.x), which form the pore of the channel, and sulfonylurea receptors (SURx), which serve as regulatory subunits (Fig. 1). SURs are members of the ATP-binding cassette protein superfamily and carry binding sites for nucleotides, sulfonylureas, and the K ATP channel openers. Both Kir6.x and SURx are encoded by two genes, giving rise to two subtypes each; in addition, alternative splicing of SUR2 results in two major isoforms, SUR2A and SUR2B, which differ in the last 42 amino acids. The K ATP channels in pancreatic ␤-cells have the composition Kir6.2/SUR1, in cardiomyocytes Kir6.2/SUR2A, and in vascular myocytes Kir6.1/SUR2B (Aguilar-Bryan and Bryan, 1999;Gribble and Reimann, 2003;Seino and Miki, 2003). K ATP channels subserve important functions not only in the pancreatic ␤-cells (in which they link the secretion of insulin to the plasma glucose level) but also in other tissues (Seino and Miki, 2003). Hence, the selectivity of the insulinotropes for the panc...

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“…Kir6.2/SUR2 channels, which already possess a tyrosine at this position, also show reversible block by glibenclamide and glimepiride. In addition, glibenclamide binding to SUR1 is greatly decreased by the S1237Y mutation (35), whereas glibenclamide binding to SUR2B is enhanced by the reverse mutation (36,37). Thus S1237 must contribute to the binding site for sulfonylureas on SUR1.…”

Section: Location Of the Sulfonylurea Binding Site On Surmentioning

confidence: 99%

Sulfonylurea Stimulation of Insulin Secretion

et al. 2002

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Sulfonylureas are widely used to treat type 2 diabetes because they stimulate insulin secretion from pancreatic ␤-cells. They primarily act by binding to the SUR subunit of the ATP-sensitive potassium (K ATP ) channel and inducing channel closure. However, the channel is still able to open to a limited extent when the drug is bound, so that high-affinity sulfonylurea inhibition is not complete, even at saturating drug concentrations. K ATP channels are also found in cardiac, skeletal, and smooth muscle, but in these tissues are composed of different SUR subunits that confer different drug sensitivities. Thus tolbutamide and gliclazide block channels containing SUR1 (␤-cell type), but not SUR2 (cardiac, smooth muscle types), whereas glibenclamide, glimepiride, repaglinide, and meglitinide block both types of channels. This difference has been exploited to determine residues contributing to the sulfonylurea-binding site. Sulfonylurea block is decreased by mutations or agents (e.g., phosphatidylinositol bisphosphate) that increase K ATP channel open probability. We now propose a kinetic model that explains this effect in terms of changes in the channel open probability and in the transduction between the drug-binding site and the channel gate. We also clarify the mechanism by which MgADP produces an apparent increase of sulfonylurea efficacy on channels containing SUR1 (but not SUR2). Diabetes 51 (Suppl. 3):S368 -S376, 2002

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Interaction of K_ATPChannel Modulators with Sulfonylurea Receptor SUR2B: Implication for Tetramer Formation and Allosteric Coupling of Subunits

Cited by 26 publications

References 36 publications

Effect of Two Amino Acids in TM17 of Sulfonylurea Receptor SUR1 on the Binding of ATP-Sensitive K+ Channel Modulators

Effect of Two Amino Acids in TM17 of Sulfonylurea Receptor SUR1 on the Binding of ATP-Sensitive K+ Channel Modulators

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

Sulfonylurea Stimulation of Insulin Secretion

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Interaction of KATPChannel Modulators with Sulfonylurea Receptor SUR2B: Implication for Tetramer Formation and Allosteric Coupling of Subunits

Cited by 26 publications

References 36 publications

Effect of Two Amino Acids in TM17 of Sulfonylurea Receptor SUR1 on the Binding of ATP-Sensitive K+ Channel Modulators

Effect of Two Amino Acids in TM17 of Sulfonylurea Receptor SUR1 on the Binding of ATP-Sensitive K+ Channel Modulators

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

Sulfonylurea Stimulation of Insulin Secretion

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Interaction of K_ATPChannel Modulators with Sulfonylurea Receptor SUR2B: Implication for Tetramer Formation and Allosteric Coupling of Subunits