Xenbase Image ID: 136570
FIG. 6. ATP modulation of gliclazide block of wild-type and mutant KATP channels. A–E: Gliclazide concentration-inhibition relations for wild-type and mutant channels in the absence (○) and presence (●) of MgATP. Currents are expressed relative to those in the absence of both MgATP and gliclazide. MgATP concentrations were 15 μmol/L (A, Kir6.2/SUR1), 100 μmol/L (B, Kir6.2-R201C/SUR1), 1 mmol/L (C, Kir6.2-G334D/SUR1), 100 μmol/L (D, Kir6.2-V59M/SUR1), and 3 mmol/L (E, Kir6.2-I296L/SUR1). The lines are the best fit of Eq. 1 to the mean data with the following parameters: Kir6.2/SUR1 (A): IC50 = 67 nmol/L, h = 1.3, a = 0.45 (○) and IC50 = 71 nmol/L, h = 1.0, a = 0.10 (●); Kir6.2-R201C/SUR1 (B): IC50 = 67 nmol/L, h = 1.1, a = 0.39 (○) and IC50 = 190 nmol/L, h = 1.2, a = 0.25 (●); Kir6.2-G334D/SUR1 (C): IC50 = 140 nmol/L, h = 0.88, a = 0.31 (○) and IC50 = 213 nmol/L, h = 1.0, a = 0.39 (●); Kir6.2-V59M/SUR1 (D): IC50 = 200 nmol/L, h = 0.92, a = 0.79 (○) and IC50 = 49 nmol/L, h = 1.2, a = 0.48 (●); and Kir6.2-I296L/SUR1 (E): IC50 = 930 nmol/L, h = 1.5, a = 0.95 (○) and IC50 = 1,200 nmol/L, h = 0.98, a = 0.38 (●). n = 6 in all experiments. Note that in the absence of gliclazide Kir6.2-G334D/SUR1 currents are greater in the presence of ATP than in the absence of ATP because the G334D mutation abolishes the inhibitory effect of ATP at Kir6.2, leaving only the stimulatory effect at SUR1 (C). In contrast, currents are smaller in the presence of MgATP for all other channels because both inhibition and activation are present. F and G: Current remaining in the presence of 100 μmol/L MgATP or 1 mmol/L MgATP in the absence (open bars) and presence (solid bars) of 30 μmol/L gliclazide for wild-type channels and KATP channels carrying ND mutations. The current is expressed as a fraction of that in drug- and nucleotide-free solution. n = 6 in all experiments. WT, wild-type.
Image published in: Proks P et al. (2013)
Image downloaded from an Open Access article in PubMed Central. © 2013 by the American Diabetes Association.
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