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. 2013 Oct 18;62(11):3909–3919. doi: 10.2337/db13-0531

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© 2013 by the American Diabetes Association.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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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 P_O 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 P_O(0) is the single-channel P_O 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 P_O at gliclazide concentrations that saturate the high-affinity SUR1 site. P_O(0) = 0.76, IC₅₀ = 440 nmol/L, h = 0.92, a = 0.47 (●) and P_O(0) = 0.59, IC₅₀ = 30 nmol/L, h = 1.0, a = 0.60 (●). D: Mean ± SEM relationship between glibenclamide and the whole-cell K_ATP 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 (I_C). 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 [●]).

Inline graphic — 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 P_O 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 P_O(0) is the single-channel P_O 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 P_O at gliclazide concentrations that saturate the high-affinity SUR1 site. P_O(0) = 0.76, IC₅₀ = 440 nmol/L, h = 0.92, a = 0.47 (●) and P_O(0) = 0.59, IC₅₀ = 30 nmol/L, h = 1.0, a = 0.60 (●). D: Mean ± SEM relationship between glibenclamide and the whole-cell K_ATP 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 (I_C). 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 [●]).