ABCMdb

PMID: 12604678

Chachin M, Yamada M, Fujita A, Matsuoka T, Matsushita K, Kurachi Y
Nateglinide, a D-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety, specifically inhibits pancreatic beta-cell-type K(ATP) channels.
J Pharmacol Exp Ther. 2003 Mar;304(3):1025-32., [PubMed]

Sentences

No. Mutations Sentence Comment

6 ABCC8 p.Ser1237Tyr 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 ABCC8 p.Ser1237Tyr ABCC8 p.Ser1237Tyr 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 8 ABCC8 p.Lys1384Ala This augmenting effect of MgADP was also observed with the SUR1/Kir6.2(K185Q) channel, which was not inhibited by MgADP, but not with the SUR1(K1384A)/Kir6.2 channel, which was not activated by MgADP. Login to comment 18 ABCC8 p.Ser1237Tyr 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 ABCC8 p.Ser1237Tyr ABCC8 p.Lys1384Ala 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 92 ABCC8 p.Ser1237Tyr Inhibitory Effect of Nateglinide on Kir6.2èc;C26 and SUR1(S1237Y)/Kir6.2 Channels. Login to comment 93 ABCC8 p.Ser1237Tyr Inhibitory Effect of Nateglinide on Kir6.2⌬C26 and SUR1(S1237Y)/Kir6.2 Channels. Login to comment 101 ABCC8 p.Ser1237Tyr Inhibitory effect of nateglinide on Kir6.2èc;C26 and SUR1(S1237Y)/Kir6.2 channel currents. Login to comment 102 ABCC8 p.Ser1237Tyr ABCC8 p.Ser1237Tyr ABCC8 p.Ser1237Tyr Inhibitory effect of nateglinide on Kir6.2⌬C26 and SUR1(S1237Y)/Kir6.2 channel currents. Login to comment 103 ABCC8 p.Ser1237Tyr ABCC8 p.Ser1237Tyr 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 105 ABCC8 p.Ser1237Tyr 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 106 ABCC8 p.Ser1237Tyr 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 107 ABCC8 p.Ser1237Tyr [SUR1(S1237Y)] abolishes the high-affinity inhibition of SUR1/Kir6.2 channels by tolbutamide (Ashfield et al., 1999). Login to comment 108 ABCC8 p.Ser1237Tyr [SUR1(S1237Y)] abolishes the high-affinity inhibition of SUR1/Kir6.2 channels by tolbutamide (Ashfield et al., 1999). Login to comment 109 ABCC8 p.Ser1237Tyr 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 110 ABCC8 p.Ser1237Tyr 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 116 ABCC8 p.Ser1237Tyr 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 117 ABCC8 p.Ser1237Tyr 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 ABCC8 p.Ser1237Tyr 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 124 ABCC8 p.Ser1237Tyr ABCC8 p.Ser1237Tyr 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 ABCC8 p.Ser1237Tyr 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 146 ABCC8 p.Lys1384Ala To test this hypothesis, we used SUR1 where lysine 1384 in the Walker A motif in nucleotide binding domain 2 was substituted with alanine [SUR1(K1384A)] (Fig. 4C). Login to comment 147 ABCC8 p.Lys1384Ala To test this hypothesis, we used SUR1 where lysine 1384 in the Walker A motif in nucleotide binding domain 2 was substituted with alanine [SUR1(K1384A)] (Fig. 4C). Login to comment 148 ABCC8 p.Lys1384Ala MgADP (100 òe;M) inhibited SUR1(K1384A)/Kir6.2 channels by 58.2 afe; 8.6 and 69.7 afe; 5.2% in the absence and presence of nateglinide (10 òe;M), re- Fig. 4. Login to comment 149 ABCC8 p.Lys1384Ala ABCC8 p.Lys1384Ala MgADP (100 ␮M) inhibited SUR1(K1384A)/Kir6.2 channels by 58.2 ee; 8.6 and 69.7 Ϯ 5.2% in the absence and presence of nateglinide (10 ␮M), re-Fig. 4. Login to comment 150 ABCC8 p.Lys1384Ala ABCC8 p.Lys1384Ala Effect of nateglinide on SUR1/Kir6.2(K185Q), SUR1/Kir6.2, and SUR1(K1384A)/Kir6.2 channels in the presence and absence of nucleotides. Login to comment 151 ABCC8 p.Lys1384Ala Effects of nateglinide on SUR1/Kir6.2(K185Q) (A), SUR1/Kir6.2 (B), and SUR1(K1384A)/Kir6.2 (C) channel currents were measured in inside-out patches. Login to comment 156 ABCC8 p.Lys1384Ala Nateglinide inhibited SUR1(K1384A)/Kir6.2 channel currents by 60.5 afe; 6.3 and 71.2 afe; 3.8% in the absence and presence of MgADP, respectively (Fig. 4D). Login to comment 157 ABCC8 p.Lys1384Ala Nateglinide inhibited SUR1(K1384A)/Kir6.2 channel currents by 60.5 Ϯ 6.3 and 71.2 Ϯ 3.8% in the absence and presence of MgADP, respectively (Fig. 4D). Login to comment 178 ABCC8 p.Ser1237Tyr The high-affinity inhibition of the channels by nateglinide was eliminated by the S1237Y mutation of SUR1 (Fig. 2A). Login to comment 179 ABCC8 p.Ser1237Tyr The high-affinity inhibition of the channels by nateglinide was eliminated by the S1237Y mutation of SUR1 (Fig. 2A). Login to comment 184 ABCC8 p.Ser1237Tyr 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 185 ABCC8 p.Ser1237Tyr 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 ABCC8 p.Ser1237Tyr 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 193 ABCC8 p.Ser1237Tyr 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