ABCMdb

ABCC8 p.Ser1237Tyr

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Publications

PMID: 19587354 [PubMed] Hamming KS et al: "Coexpression of the type 2 diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonylurea sensitivities of the ATP-sensitive K(+) channel."

No. Sentence Comment

76 The A site is located close to SUR1 transmembrane segments 14-16, and the S1237Y mutation in this region (Fig. 3A) abolishes A-site drug inhibition (18). Login to comment
78 The A site is located close to SUR1 transmembrane segments 14-16, and the S1237Y mutation in this region (Fig. 3A) abolishes A-site drug inhibition (18). Login to comment

PMID: 12023875 [PubMed] Gribble FM et al: "Pharmacological modulation of K(ATP) channels."

No. Sentence Comment

94 However, the high-affinity blocking of Kir6.2/SURl channels by nateglinide and mitiglinide, which both show homology with meglitinide, has recently been reported to be abolished by the S1237Y mutation in SURl (see below), rather unexpectedly suggesting that their binding site overlaps with that of the sulphonylureas [37,38]. Login to comment
95 However, the high-affinity blocking of Kir6.2/SURl channels by nateglinide and mitiglinide, which both show homology with meglitinide, has recently been reported to be abolished by the S1237Y mutation in SURl (see below), rather unexpectedly suggesting that their binding site overlaps with that of the sulphonylureas [37,38]. Login to comment

PMID: 15561897 [PubMed] Bryan J et al: "Toward linking structure with function in ATP-sensitive K+ channels."

No. Sentence Comment

132 Substitution of Ser1237 with Tyr, the analogous residue in SUR2, reduced the apparent affinity of SUR1 for tolbutamide and glibenclamide (82). Login to comment

PMID: 12623163 [PubMed] Gribble FM et al: "Differential selectivity of insulin secretagogues: mechanisms, clinical implications, and drug interactions."

No. Sentence Comment

67 The difference between SUR1 and SUR2 that accounts for the different sensitivities to KATP channel inhibitors has been localised to the TM15-16 loop, in which a single amino acid substitution (S1237Y) in SUR1 is sufficient to abolish the action of tolbutamide on channel activity and to prevent binding of [3 H]glibenclamide (Ashfield et al., 1999). Login to comment
69 The actions of meglitinide and repaglinide on Kir6.2/SUR1 currents are not affected by the S1237Y mutation (Ashfield et al., 1999; Dabrowski et al., 2001), supporting the idea that a different region of the binding site (e.g., the TMs 5-6 loop) is involved. Login to comment
71 Inability to bind to the TMs 15-16 loop, either in SUR2 or SUR1-S1237Y, accounts for the rapid reversibility of glibenclamide and glimepiride in these cases. Login to comment
72 The slow reversibility of repaglinide cannot be explained on the same basis, as it is unaffected by the SUR type or the S1237Y mutation in SUR1, and is likely to be attributable to its greater hydrophobicity. Login to comment

PMID: 12562963 [PubMed] Reimann F et al: "Analysis of the differential modulation of sulphonylurea block of beta-cell and cardiac ATP-sensitive K+ (K(ATP)) channels by Mg-nucleotides."

No. Sentence Comment

124 The binding sites for these drugs are not, however, believed to be identical, as the mutation S1237Y in SUR1 abolishes tolbutamide, but not meglitinide, inhibition (Ashfield et al. 1999). Login to comment
158 The cytosolic loop linking TMs 15 and 16 has been shown to play a role in sulphonylurea binding to SUR1, as mutation of S1237Y abolished tolbutamide block and [3 H]glibenclamide binding, whilst inhibition by meglitinide(whichresemblesthenon-sulphonylureamoiety of glibenclamide) was unaffected (Ashfield et al. 1999). Login to comment

PMID: 12604678 [PubMed] Chachin M et al: "Nateglinide, a D-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety, specifically inhibits pancreatic beta-cell-type K(ATP) channels."

No. Sentence Comment

6 Replacement of serine at position 1237 of SUR1 to tyrosine [SUR1(S1237Y)] specifically abolished the high-affinity inhibition of SUR1/Kir6.2 channels by nateglinide. Login to comment
7 MgADP or MgUDP (100 ␮M) augmented the inhibitory effect of nateglinide on SUR1/Kir6.2 but not SUR1(S1237Y)/Kir6.2 or SUR2A/Kir6.2 channels. Login to comment
18 In preparation of this manuscript, Hansen et al. (2002) reported that nateglinide inhibits SUR1/Kir6.2 channels with the half-maximum inhibitory concentration of 800 nM and that this inhibition is abolished by the S1237Y mutation of SUR1, consistent with our present observations. Login to comment
36 SUR1 whose serine at position 1237 was substituted with tyrosine [SUR1(S1237Y)], SUR1 whose lysine at position 1384 was substituted with alanine [SUR1(K1384A)], and Kir6.2 whose lysine at position 185 was substituted with glutamine [Kir6.2(K185Q)] were constructed using the GeneEditor in vitro site-directed mutagenesis system (Promega, Madison, WI). Login to comment
93 Inhibitory Effect of Nateglinide on Kir6.2⌬C26 and SUR1(S1237Y)/Kir6.2 Channels. Login to comment
102 Inhibitory effect of nateglinide on Kir6.2⌬C26 and SUR1(S1237Y)/Kir6.2 channel currents. Login to comment
103 Left column, inhibitory effects of nateglinide on spontaneously opening Kir6.2⌬C26 (A) and SUR1(S1237Y)/Kir6.2 (B) channels were measured at -60 mV in inside-out patches. ATP and nateglinide were added to the bath solution as indicated by bars. Right column, concentration-response relationships for inhibition of Kir6.2⌬C26 (A) and SUR1(S1237Y)/Kir6.2 (B) channel currents by nateglinide. Login to comment
106 The lines were fit with the single-site model with Ki2 ϭ 290 ␮M and h2 ϭ 0.9 for Kir6.2⌬C26 channels, and Ki2 ϭ 72 ␮M and h2 ϭ 0.7 for SUR1(S1237Y)/Kir6.2 channels. Login to comment
108 [SUR1(S1237Y)] abolishes the high-affinity inhibition of SUR1/Kir6.2 channels by tolbutamide (Ashfield et al., 1999). Login to comment
110 Nateglinide inhibited SUR1(S1237Y)/ Kir6.2 channel currents only with low-affinity (Ki2 ϭ 72 ␮M), indicating that the same amino acid residue in SUR1 mediates the high-affinity inhibition of SUR1/Kir6.2 channels by nateglinide and tolbutamide. Login to comment
117 To examine whether the potentiation by MgADP of the effect of nateglinide upon SUR1/Kir6.2 was related to the high-affinity site for the drug, we repeated the experiment using SUR1(S1237Y)/Kir6.2 channels (Fig. 3B). Login to comment
124 Effect of nateglinide on SUR1/Kir6.2, SUR1(S1237Y)/Kir6.2, and SUR2A/Kir6.2 channels in the presence and absence of 100 ␮M MgADP. Login to comment
125 The inhibitory effects of nateglinide on SUR1/Kir6.2 (A), SUR1(S1237Y)/Kir6.2 (B), and SUR2A/Kir6.2 (C) channels were measured in inside-out patches. ATP, ADP, and nateglinide were added to the bath solution as indicated by bars. Login to comment
179 The high-affinity inhibition of the channels by nateglinide was eliminated by the S1237Y mutation of SUR1 (Fig. 2A). Login to comment
185 Mitiglinide is another antidiabetic agent that lacks either a sulfonylurea or benzamido moiety but causes high-affinity inhibition of SUR1/Kir6.2 channels that is abolished by the S1237Y mutation (Reimann et al., 2001). Login to comment
193 Although nateglinide lacks a sulfonylurea moiety, its effect on SUR1/ Kir6.2 channels resembles that of tolbutamide with respect to the S1237Y mutation and the interaction with intracellular MgADP. Login to comment
92 Inhibitory Effect of Nateglinide on Kir6.2èc;C26 and SUR1(S1237Y)/Kir6.2 Channels. Login to comment
101 Inhibitory effect of nateglinide on Kir6.2èc;C26 and SUR1(S1237Y)/Kir6.2 channel currents. Login to comment
105 The lines were fit with the single-site model with Ki2 afd; 290 òe;M and h2 afd; 0.9 for Kir6.2èc;C26 channels, and Ki2 afd; 72 òe;M and h2 afd; 0.7 for SUR1(S1237Y)/Kir6.2 channels. Login to comment
107 [SUR1(S1237Y)] abolishes the high-affinity inhibition of SUR1/Kir6.2 channels by tolbutamide (Ashfield et al., 1999). Login to comment
109 Nateglinide inhibited SUR1(S1237Y)/ Kir6.2 channel currents only with low-affinity (Ki2 afd; 72 òe;M), indicating that the same amino acid residue in SUR1 mediates the high-affinity inhibition of SUR1/Kir6.2 channels by nateglinide and tolbutamide. Login to comment
116 To examine whether the potentiation by MgADP of the effect of nateglinide upon SUR1/Kir6.2 was related to the high-affinity site for the drug, we repeated the experiment using SUR1(S1237Y)/Kir6.2 channels (Fig. 3B). Login to comment
123 Effect of nateglinide on SUR1/Kir6.2, SUR1(S1237Y)/Kir6.2, and SUR2A/Kir6.2 channels in the presence and absence of 100 òe;M MgADP. Login to comment
178 The high-affinity inhibition of the channels by nateglinide was eliminated by the S1237Y mutation of SUR1 (Fig. 2A). Login to comment
184 Mitiglinide is another antidiabetic agent that lacks either a sulfonylurea or benzamido moiety but causes high-affinity inhibition of SUR1/Kir6.2 channels that is abolished by the S1237Y mutation (Reimann et al., 2001). Login to comment
192 Although nateglinide lacks a sulfonylurea moiety, its effect on SUR1/ Kir6.2 channels resembles that of tolbutamide with respect to the S1237Y mutation and the interaction with intracellular MgADP. Login to comment

PMID: 12819907 [PubMed] Gribble FM et al: "Sulphonylurea action revisited: the post-cloning era."

No. Sentence Comment

130 The binding site for sulphonylureas and glinides could therefore be envisaged as a pocket with at least two binding motifs, one (exclusive to SUR1 and abolished by the S1237Y mutation) favouring sulphonylurea groups, and the other (common to SUR1 and SUR2) preferring meglitinide-like molecules [4, 44, 91]. Login to comment
135 In line with this idea, mutation of S1237Y in SUR1 increased glibenclamide reversibility in patch clamp experiments and impaired the binding of [3H]glibenclamide [49, 91], whereas the reverse mutation (Y1206S) in SUR2B increased the [3H]glibenclamide binding affinity [92]. Login to comment
136 Neither repaglinide reversibility, nor binding of [3H]repaglinide, were affected by the S1237Y mutation in SUR1 [47, 49]. Login to comment
154 Thus, they both inhibited Kir6.2/SUR1 with higher affinity than Kir6.2/SUR2 currents, and inhibition of SUR1-type channels was impaired by the S1237Y mutation [48, 49, 50, 97]. Login to comment

PMID: 15678092 [PubMed] Hansen AM et al: "Kir6.2-dependent high-affinity repaglinide binding to beta-cell K(ATP) channels."

No. Sentence Comment

28 Recent studies from our laboratory suggested that the binding site for repaglinide is not identical to that of sulphonylureas, since repaglinide binding and channel inhibition by this drug were unaffected by mutation S1237Y in SUR1, which abolishes KATP channel inhibition by tolbutamide (Hansen et al., 2002). Login to comment

PMID: 12475777 [PubMed] Proks P et al: "Sulfonylurea stimulation of insulin secretion."

No. Sentence Comment

124 The curves are fit to equation 2. beta-cell KATP channels, is not easily reversed in electrophysiological recordings, whereas glibenclamide block is rapidly reversed when SUR1 contains the S1237Y mutation. Login to comment
126 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). Login to comment
129 The fact that glibenclamide blocks Kir6.2/SUR1-S1237Y channels indicates that residues other than S1237 are critical for binding of this drug. Login to comment
130 Likewise, the block of Kir6.2/SUR1 by meglitinide and repaglinide, which do not possess a sulfonylurea moiety, is unaltered by the S1237Y mutation (35,53), suggesting that these drugs do not interact with this residue. Login to comment
123 The curves are fit to equation 2. beta-cell KATP channels, is not easily reversed in electrophysiological recordings, whereas glibenclamide block is rapidly reversed when SUR1 contains the S1237Y mutation. Login to comment
125 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). Login to comment
128 The fact that glibenclamide blocks Kir6.2/SUR1-S1237Y channels indicates that residues other than S1237 are critical for binding of this drug. Login to comment

PMID: 16956886 [PubMed] Yan FF et al: "Sulfonylureas correct trafficking defects of disease-causing ATP-sensitive potassium channels by binding to the channel complex."

No. Sentence Comment

105 If sulfonylureas rescue the A116P and V187D trafficking mutants by binding to the channel protein, then introducing the S1237Y mutation should also reduce or abolish the ability of sulfonylureas to correct the trafficking defect. Login to comment

PMID: 12196472 [PubMed] Hansen AM et al: "Differential interactions of nateglinide and repaglinide on the human beta-cell sulphonylurea receptor 1."

No. Sentence Comment

3 Mutation of serine 1237 in SUR1 to tyrosine (S1237Y) abolished tolbutamide and nateglinide block, suggesting that these drugs share a common point of interaction on the SUR1 subunit of the ATP-sensitive K؉ channel. Login to comment
4 In contrast, repaglinide inhibition was unaffected by the S1237Y mutation (IC50 ‫؍‬ 23 nmol/l). Login to comment
7 This is consistent with the idea that binding of nateglinide and tolbutamide, but not repaglinide, is abolished by the SUR1[S1237Y] mutation and that the binding site for repaglinide is not identical to that of nateglinde/tolbutamide. Login to comment
34 SUR1 currents by the nonsulphonylurea mitiglinide, as with tolbutamide, is abolished by the S1237Y mutation (16). Login to comment
45 The point mutation SUR1[S1237Y] was constructed by standard molecular biology techniques and confirmed by DNA sequencing. Login to comment
48 Cells were seeded at 50% confluency and transfected with Kir6.2 and SUR1[S1237Y] at a plasmid ratio of 1:3 on the next day. Login to comment
63 Binding experiments were performed in triplicate (Kir6.2/SUR1) or duplicate (Kir6.2/SUR1[S1237Y]). Login to comment
92 RESULTS Electrophysiology. Whole-cell currents were recorded from HEK293 cells coexpressing Kir6.2 and either SUR1 or SUR1[S1237Y]. Login to comment
93 After establishment of the whole-cell configuration and dialysis with intracellular solution, there was a gradual increase in both Kir6.2/SUR1 and Kir6.2/ SUR1[S1237Y] currents due to opening of KATP channels. Login to comment
95 In contrast, tolbutamide had very little effect on Kir6.2/SUR1[S1237Y] currents (Fig. 1B). Login to comment
97 Although glibenclamide also inhibited Kir6.2/SUR1[S1237Y] channels (by 67 Ϯ 6%; n ϭ 3), in this case, inhibition was largely reversed on wash-out of the drug (Fig. 1B). Login to comment
101 A similar extent of block was observed for Kir6.2/ SUR1[S1237Y] (94 Ϯ 1%, n ϭ 4) (Fig. 2B), suggesting that S1237 is not required for repaglinide inhibition. Login to comment
103 In contrast, nateglinide (100 ␮mol/l) produced reversible inhibition of Kir6.2/SUR1 currents (96 Ϯ 2%, n ϭ 4) (Fig. 2A) but was without significant effect on Kir6.2/SUR1[S1237Y] channels (Fig. 2B). Login to comment
105 Repaglinide blocked Kir6.2/SUR1 and Kir6.2/SUR1[S1237Y] currents with similar potency: IC50 ϭ 21 nmol/l (95% CI 17-26) and IC50 ϭ 23 nmol/l (18-28), respectively. Login to comment
114 Similarly, binding of [3 H]repaglinide to Kir6.2/SUR1[S1237Y] revealed a single binding site (Fig. 4B) with a KD of 0.31 Ϯ 0.02 nmol/l and a Bmax of 1.6 Ϯ 0.2 pmol/mg protein (n ϭ 3). Login to comment
118 HEK 293 cells expressing Kir6.2/SUR1 (A) or Kir6.2/SUR1[S1237Y] (B) channels were clamped at -70 mV. Login to comment
122 HEK 293 cells expressing Kir6.2/SUR1 (A) or Kir6.2/ SUR1[S1237Y] (B) channels were clamped at -70 mV. Login to comment
125 Concentration-response curves for inhibition of Kir6.2/SUR1 (f/F) and Kir6.2/SUR1[S1237Y] (Ⅺ/E) channels by repaglinide (f/Ⅺ) or nateglinide (F/E). Login to comment
130 We therefore examined the ability of unlabelled nateglinide to displace [3 H]repaglinide binding to membranes isolated from HEK293 cells expressing Kir6.2/SUR1 or Kir6.2/SUR1[S1237Y]. Login to comment
137 In the case of Kir6.2/SUR1[S1237Y], repaglinide displaced [3 H]repaglinide binding with a Ki of 0.4 Ϯ 0.2 nmol/l (n ϭ 3), which is similar to that found for the wild-type channel. Login to comment
141 The data are consistent with the idea that the nateglinide binding, as with that of tolbutamide, is abolished by the S1237Y mutation in SUR1. Login to comment
147 Saturation binding of [3 H]repaglinide to membranes prepared from HEK 293 cells expressing Kir6.2/SUR1 (A) or Kir6.2/ SUR1[S1237Y] (B). Login to comment
148 Data are from a single representative experiment in which data points were collected in triplicate (Kir6.2/SUR1) or duplicate (Kir6.2/SUR1[S1237Y]). Login to comment
150 Competition binding to membranes from HEK 293 cells expressing Kir6.2/SUR1 (A) or Kir6.2/SUR1[S1237Y] (B). Login to comment
153 Data are from a single representative experiment in which data points were collected in triplicate (Kir6.2/SUR1) or duplicate (Kir62/SUR1[S1237Y]). Login to comment
179 TABLE 1 Comparison of [3 H]repaglinide binding data on Kir6.2/SUR1 and Kir6.2/SUR1[S1237Y] Compound Kir6.2/SUR1 Kir6.2/SUR1[S1237Y] IC50 (nmol/l) nH Ki (nmol/l) IC50 (nmol/l) nH Ki (nmol/l) Repaglinide 1.9 Ϯ 0.8 -1.19 Ϯ 0.10 0.6 Ϯ 0.3 1.2 Ϯ 0.7 -1.05 Ϯ 0.14 0.4 Ϯ 0.2 Glibenclamide 0.7 Ϯ 0.2 -1.14 Ϯ 0.13 0.2 Ϯ 0.1 105 Ϯ 17 -0.90 Ϯ 0.25 36 Ϯ 6 Nateglinide 679 Ϯ 121 -0.98 Ϯ 0.05 235 Ϯ 42 Ͼ30,000 N/A N/A Tolbutamide 26,000 Ϯ 9,300 -0.91 Ϯ 0.12 9,000 Ϯ 3,220 Ͼ300,000 N/A N/A Data are means Ϯ SD (n ϭ 3). Login to comment
181 Glibenclamide produced a reversible block of Kir6.2/ SUR1[S1237Y]. Login to comment
184 Thus, glibenclamide displaced [3 H]repaglinide binding to the mutant channel with a much lower potency than for the wild-type channel, consistent with a larger dissociation rate constant for glibenclamide binding to Kir6.2/SUR1[S1237Y]. Login to comment
188 This suggests that the binding affinity of repaglinide is enhanced by interaction with additional residues in SUR1 and that this interaction is not disrupted by the S1237Y mutation. Login to comment
189 The effect of the S1237Y mutation on nateglinide-induced KATP channel inhibition could be due to either reduced drug binding or an impaired ability of SUR1 to transduce drug binding into channel closure. Login to comment
190 However, because Kir6.2/SUR1[S1237Y] retains the ability to be blocked fully by repaglinide and glibenclamide, the transduction mechanism does not appear to be compromised by the mutation. Login to comment
35 SUR1 currents by the nonsulphonylurea mitiglinide, as with tolbutamide, is abolished by the S1237Y mutation (16). Login to comment
46 The point mutation SUR1[S1237Y] was constructed by standard molecular biology techniques and confirmed by DNA sequencing. Login to comment
49 Cells were seeded at 50% confluency and transfected with Kir6.2 and SUR1[S1237Y] at a plasmid ratio of 1:3 on the next day. Cells to be used for electrophysiological experiments were also cotransfected with green fluorescent protein (GFP) to enable visual identification of transfected cells. Login to comment
64 Binding experiments were performed in triplicate (Kir6.2/SUR1) or duplicate (Kir6.2/SUR1[S1237Y]). Login to comment
94 After establishment of the whole-cell configuration and dialysis with intracellular solution, there was a gradual increase in both Kir6.2/SUR1 and Kir6.2/ SUR1[S1237Y] currents due to opening of KATP channels. Login to comment
96 In contrast, tolbutamide had very little effect on Kir6.2/SUR1[S1237Y] currents (Fig. 1B). Login to comment
98 Although glibenclamide also inhibited Kir6.2/SUR1[S1237Y] channels (by 67 afe; 6%; n afd; 3), in this case, inhibition was largely reversed on wash-out of the drug (Fig. 1B). Login to comment
102 A similar extent of block was observed for Kir6.2/ SUR1[S1237Y] (94 afe; 1%, n afd; 4) (Fig. 2B), suggesting that S1237 is not required for repaglinide inhibition. Login to comment
104 In contrast, nateglinide (100 òe;mol/l) produced reversible inhibition of Kir6.2/SUR1 currents (96 afe; 2%, n afd; 4) (Fig. 2A) but was without significant effect on Kir6.2/SUR1[S1237Y] channels (Fig. 2B). Login to comment
106 Repaglinide blocked Kir6.2/SUR1 and Kir6.2/SUR1[S1237Y] currents with similar potency: IC50 afd; 21 nmol/l (95% CI 17-26) and IC50 afd; 23 nmol/l (18-28), respectively. Login to comment
115 Similarly, binding of [3 H]repaglinide to Kir6.2/SUR1[S1237Y] revealed a single binding site (Fig. 4B) with a KD of 0.31 afe; 0.02 nmol/l and a Bmax of 1.6 afe; 0.2 pmol/mg protein (n afd; 3). Login to comment
119 HEK 293 cells expressing Kir6.2/SUR1 (A) or Kir6.2/SUR1[S1237Y] (B) channels were clamped at d1a;70 mV. Login to comment
123 HEK 293 cells expressing Kir6.2/SUR1 (A) or Kir6.2/ SUR1[S1237Y] (B) channels were clamped at d1a;70 mV. Login to comment
126 Concentration-response curves for inhibition of Kir6.2/SUR1 (f/F) and Kir6.2/SUR1[S1237Y] (ǧa;/E) channels by repaglinide (f/ǧa;) or nateglinide (F/E). Login to comment
131 We therefore examined the ability of unlabelled nateglinide to displace [3 H]repaglinide binding to membranes isolated from HEK293 cells expressing Kir6.2/SUR1 or Kir6.2/SUR1[S1237Y]. Login to comment
138 In the case of Kir6.2/SUR1[S1237Y], repaglinide displaced [3 H]repaglinide binding with a Ki of 0.4 afe; 0.2 nmol/l (n afd; 3), which is similar to that found for the wild-type channel. Login to comment
142 The data are consistent with the idea that the nateglinide binding, as with that of tolbutamide, is abolished by the S1237Y mutation in SUR1. Login to comment
149 Data are from a single representative experiment in which data points were collected in triplicate (Kir6.2/SUR1) or duplicate (Kir6.2/SUR1[S1237Y]). Login to comment
151 Competition binding to membranes from HEK 293 cells expressing Kir6.2/SUR1 (A) or Kir6.2/SUR1[S1237Y] (B). Login to comment
154 Data are from a single representative experiment in which data points were collected in triplicate (Kir6.2/SUR1) or duplicate (Kir62/SUR1[S1237Y]). Login to comment
180 TABLE 1 Comparison of [3 H]repaglinide binding data on Kir6.2/SUR1 and Kir6.2/SUR1[S1237Y] Compound Kir6.2/SUR1 Kir6.2/SUR1[S1237Y] IC50 (nmol/l) nH Ki (nmol/l) IC50 (nmol/l) nH Ki (nmol/l) Repaglinide 1.9 afe; 0.8 afa;1.19 afe; 0.10 0.6 afe; 0.3 1.2 afe; 0.7 afa;1.05 afe; 0.14 0.4 afe; 0.2 Glibenclamide 0.7 afe; 0.2 afa;1.14 afe; 0.13 0.2 afe; 0.1 105 afe; 17 afa;0.90 afe; 0.25 36 afe; 6 Nateglinide 679 afe; 121 afa;0.98 afe; 0.05 235 afe; 42 b0e;30,000 N/A N/A Tolbutamide 26,000 afe; 9,300 afa;0.91 afe; 0.12 9,000 afe; 3,220 b0e;300,000 N/A N/A Data are means afe; SD (n afd; 3). Login to comment
182 Glibenclamide produced a reversible block of Kir6.2/ SUR1[S1237Y]. Login to comment
185 Thus, glibenclamide displaced [3 H]repaglinide binding to the mutant channel with a much lower potency than for the wild-type channel, consistent with a larger dissociation rate constant for glibenclamide binding to Kir6.2/SUR1[S1237Y]. Login to comment
191 However, because Kir6.2/SUR1[S1237Y] retains the ability to be blocked fully by repaglinide and glibenclamide, the transduction mechanism does not appear to be compromised by the mutation. Login to comment

PMID: 15652236 [PubMed] Conseil G et al: "Role of two adjacent cytoplasmic tyrosine residues in MRP1 (ABCC1) transport activity and sensitivity to sulfonylureas."

No. Sentence Comment

41 Binding of [3 H]glibenclamide to membranes expressing SUR1-S1237Y is abolished concomitantly with the loss of high-affinity tolbutamide block. Login to comment

PMID: 11264248 [PubMed] Reimann F et al: "Effects of mitiglinide (S 21403) on Kir6.2/SUR1, Kir6.2/SUR2A and Kir6.2/SUR2B types of ATP-sensitive potassium channel."

No. Sentence Comment

8 5 Kir6.2/SUR1-S1237Y currents, which previously have been shown to lack high anity tolbutamide inhibition, resembled Kir6.2/SUR2 currents in being unaected by 100 nM but blocked by 10 mM mitiglinide. Login to comment
45 A mutant form of SUR1 (SUR1-S1237Y) and a truncated form of Kir6.2 (Kir6.2DC36), which lacks the C-terminal 36 amino acids and forms functional channels in the absence of SUR, were prepared as described previously (Ash®eld et al., 1999; Tucker et al., 1997). Login to comment
110 We next investigated whether mitiglinide binds to the same (or an overlapping) site on SUR1 as tolbutamide, by examining the eect of mitiglinide on channels containing a mutant form of SUR1, SUR1-S1237Y. Login to comment
112 As shown in Figure 5, Kir6.2/ SUR1-S1237Y currents were unaected by 100 nM mitiglinide but were blocked by 65.5+3.0% (n=9) in the presence of 10 mM of the drug. Login to comment
113 There was no signi®cant dierence in the extent of inhibition of Kir6.2/SUR1, Kir6.2/SUR1-S1237Y or KIR6.2/SUR2A currents produced by 10 mM mitiglinide. Login to comment
114 However, the block of Kir6.2/SUR1-S1237Y currents was readily reversible, which is in contrast to the block of Kir6.2/SUR1 currents but similar that of Kir6.2/ SUR2-type currents. Login to comment
123 SUR1 containing the mutation S1237Y lacks both high-anity tolbutamide block and [3 H]-glibenclamide binding (Ash®eld et al., 1999). Login to comment
124 We found that Kir6.2/SUR1-S1237Y channels were blocked by less than 10% by 100 nM mitiglinide, a concentration that saturates the high-anity site on SUR1. Login to comment
126 In contrast, 10 mM mitiglinide blocked Kir6.2/SUR1-S1237Y channels as much as Kir6.2/SUR1 and Kir6.2/SUR2A channels, but Kir6.2DC channels were not aected by this drug concentration. Login to comment
127 This further suggests that mitiglinide binds with intermediate anity to a site that is common to SUR1-S1237Y and SUR2. Login to comment
129 In contrast, the intermediate-anity block of Kir6.2/SUR2A, Kir6.2/SUR2B and Kir6.2/SUR1-S1237Y currents was readily reversible. Login to comment
144 In contrast to the wild-type channel, Kir6.2/SUR1-S1237Y channels are blocked to a similar extent by 10 mM meglitinide and 10 mM mitiglinide (*65%; this study and Ash®eld et al., 1999). Login to comment
158 This conclusion is based on experiments in which the drug was applied to the intracellular surface of excised membrane patches and therefore should not be extrapolated directly to the whole-cell condition, because cytosolic substances may modify the drug properties (e.g. Ventakesh et al., 1991; Kir6.2/SUR1-S1237Y Figure 5 Inhibition of Kir6.2/SUR1-S1237Y currents by S21403. Login to comment
159 (A) Macroscopic currents recorded from inside-out patches in response to a series of voltage ramps from 7110 to +100 mV from oocytes expressing Kir6.2 and SUR1-S1237Y. Login to comment

PMID: 17495126 [PubMed] Winkler M et al: "Testing the bipartite model of the sulfonylurea receptor binding site: binding of A-, B-, and A + B-site ligands."

No. Sentence Comment

5 A-ligands are highly selective in closing the pancreatic channel, whereas B-ligands are nonselective and insensitive to the mutation S1237Y. Login to comment
33 In addition, their potency in closing the pancreatic channel was not affected by the mutation S1237Y in SUR1 (Ashfield et al., 1999; Hansen et al., 2002). Login to comment
39 We evaluated the effect of coexpression with Kir6.x on the affinity of SURx for the insulinotropes, the effect of the mutation SUR2(Y1206S), i.e., the reverse of the mutation SUR1(S1237Y), and the selectivity in binding to the recombinant pancreatic, myocardial, and vascular KATP channels. Login to comment

PMID: 10342826 [PubMed] Ashfield R et al: "Identification of the high-affinity tolbutamide site on the SUR1 subunit of the K(ATP) channel."

No. Sentence Comment

4 High-affinity tolbutamide inhibition could be conferred on SUR2A by replacing transmembrane domains (TMs) 14-16 with the corresponding region of SUR1. Conversely, high-affinity tolbutamide inhibition of SUR1 was abolished by replacing TMs 13-16 with the corresponding SUR2A sequence, or by mutating a single serine residue within this region to tyrosine (S1237Y). Login to comment
32 alent region of SUR2A or by a mutation within this region (S1237Y). Login to comment
138 While MgADP did not promote tolbutamide inhibition of Kir6.2-SUR1(S1237Y) currents, the nucleotide was able to enhance meglitinideblock(Fig. 4). Login to comment
145 The dashed lines indicate the data for Kir6.2-SUR1 and Kir6.2-SUR2A given in A and B. D: Kir6.2-SUR1(S1237Y) currents were fit with equation 4: Ki1 = 1.3 mmol/l, h1 = .9, L = 0 (n = 5). Login to comment
153 We comparedthe binding of [3 H]glibenclamide to SUR1, SUR12-e, and SUR1(S1237Y) expressed in Cos7 cells, and evaluatedprotein expression by immunoblotting with the M2 anti-FLAG antibody (Fig. 6). Login to comment
154 Binding of [3 H]glibenclamide to SUR12-e or SUR1(S1237Y) was not significantly greater than that found inuntransfected cells. Login to comment
158 High-affinity tolbutamide inhibition could be conferred on SUR2A by replacing TMs 14-16 with the equivalent region of SUR1. Conversely, the reverse chimera, or a mutation (S1237Y) within this region of SUR1, abolished both high-affinity tolbutamide block and [3 H]glibenclamide binding. Login to comment
169 Effects of tolbutamide (A) or meglitinide (B) in the presence or absence of 100 µmol/l MgADP, for channels comprising Kir6.2 and either SUR1, SUR2A, or SUR1(S1237Y). Login to comment
179 Oocytes were coinjected with mRNAs encoding Kir6.2 and either SUR1, SUR2A, SUR12-e, SUR21-x, or SUR1(S1237Y). Login to comment
194 This can be most simply explained if the S1237Y mutation specifically impaired tolbutamide binding, without interfering with either meglitinide binding or the mechanism by which sulfonylureas interfere with channel activation by MgADP. Login to comment
198 Thus, when SUR1 was rendered insensitive to tolbutamide [SUR12-e or SUR1(S1237Y)], glibenclamide block became reversible, while endowment of SUR2A with tolbutamide sensitivity (SUR21-x) was accompanied by irreversible glibenclamide inhibition. Login to comment
206 A: Membranes from Cos7 cells expressing SUR1, SUR12-e, or SUR1(S1237Y) were separated by SDS polyacrylamide gel electrophoresis, and probed with the anti-FLAG monoclonal antibody M2. Login to comment
208 B: [3 H]glibenclamide binding to membranes from Cos7 cells transfected with SUR1, SUR12-e, or SUR1(S1237Y) or to untransfected cells. Login to comment
220 In support of this view, we found that SUR12-e and SUR1(S1237Y), which form KATP channels that are blocked reversibly by glibenclamide, did not exhibit significant [3 H]glibenclamide binding. Login to comment
224 Conversely, high-affinity tolbutamide block and [3 H]glibenclamide binding were abolished by the reverse chimera or by mutation of a single amino acid, S1237Y, in the intracellular loop between TMs 15 and 16 of SUR1. Login to comment