ABCMdb

PMID: 11264248

Reimann F, Proks P, Ashcroft FM
Effects of mitiglinide (S 21403) on Kir6.2/SUR1, Kir6.2/SUR2A and Kir6.2/SUR2B types of ATP-sensitive potassium channel.
Br J Pharmacol. 2001 Apr;132(7):1542-8., [PubMed]

Sentences

No. Mutations Sentence Comment

8 ABCC8 p.Ser1237Tyr 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 ABCC8 p.Ser1237Tyr 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 ABCC8 p.Ser1237Tyr 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 ABCC8 p.Ser1237Tyr 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 ABCC8 p.Ser1237Tyr 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 ABCC8 p.Ser1237Tyr 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 ABCC8 p.Ser1237Tyr 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 ABCC8 p.Ser1237Tyr 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 ABCC8 p.Ser1237Tyr 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 ABCC8 p.Ser1237Tyr This further suggests that mitiglinide binds with intermediate anity to a site that is common to SUR1-S1237Y and SUR2. Login to comment 129 ABCC8 p.Ser1237Tyr 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 ABCC8 p.Ser1237Tyr 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 ABCC8 p.Ser1237Tyr ABCC8 p.Ser1237Tyr 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 ABCC8 p.Ser1237Tyr (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