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FIG. 7. Reduction of gliclazide block by nucleotides. A: Mean ± SEM current remaining in the presence of 100 nmol/L gliclazide and nucleotides (n = 6) for Kir6.2-G334D/SUR1 or Kir6.2-G334D/SUR1-KAKA (KAKA) channels. B: Fractional block of Kir6.2-G334D/SUR1-KAKA currents as a function of gliclazide concentration in the absence (○; n = 6) and presence (●; n = 6) of 1 mmol/L MgATP or 1 mmol/L MgADP (▲; n = 6) and in the absence (□; n = 6) and presence (■; n = 6) of 1 mmol/L ATP (Mg-free solution). The lines are the best fit of Eq. 1 to the mean data with the following parameters: IC50 = 63 nmol/L, h = 1.1, a = 0.42 (○); IC50 = 15 nmol/L, h = 1.2, a = 0.46 (●); IC50 = 75 nmol/L, h = 1.2, a = 0.42 (▲); IC50 = 64 nmol/L, h = 1.2, a = 0.29 (□); and IC50 = 67 nmol/L, h = 1.2, a = 0.29 (■). A and B: Experiments were performed in the inside-out patch configuration. C: Dependence of single-channel PO on gliclazide concentration for Kir6.2-G334D/SUR1 channels (control [●]; n = 6) and Kir6.2-G334D/SUR1-KAKA channels (KAKA [○]; n = 6) measured in cell-attached patches. The lines are the best fit of the following to the mean data: , where PO(0) is the single-channel PO in the absence of gliclazide, [X] is the gliclazide concentration, IC50 is the gliclazide concentration at which the inhibition is half maximal, h is the Hill coefficient, and a is the fractional PO at gliclazide concentrations that saturate the high-affinity SUR1 site. PO(0) = 0.76, IC50 = 440 nmol/L, h = 0.92, a = 0.47 (●) and PO(0) = 0.59, IC50 = 30 nmol/L, h = 1.0, a = 0.60 (●). D: Mean ± SEM relationship between glibenclamide and the whole-cell KATP current measured in β-cells from control mice (○; n = 6 cells, three mice) and mice in which the Kir6.2-V59M mutation was induced (V59M [●]; n = 6 cells, three mice). Current (I) is expressed relative to that in drug-free solution (IC). The curves are the best fit of Eq. 2 to the mean data with the following parameters: IC50(1) = 2 nmol/L, h1 = 1.3, IC50(2) = 45 μmol/L, h2 = 1, a = 0.03 (control [○]) and IC50(1) = 6 nmol/L, h1 = 0.74, IC50(2) = 80 μmol/L, h2 = 1, a = 0.1 (V59M [●]). Image published in: Proks P et al. (2013) © 2013 by the American Diabetes Association. This image is reproduced with permission of the journal and the copyright holder. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives license Larger Image Printer Friendly View |