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FIG. 5. ATP modulation of gliclazide block of mutant KATP channels with impaired gating. A and B: Gliclazide concentration-inhibition relations for Kir6.2-V59M/SUR1 (n = 6) and Kir6.2-I296L/SUR1 (n = 6) channels in the absence (○) and presence (●) of MgATP. The MgATP concentration was 100 μmol/L for Kir6.2-V59M/SUR1 and 3 mmol/L for Kir6.2-I296L/SUR1. The lines are the best fit of Eq. 1 to the mean data with the following parameters: Kir6.2-V59M/SUR1 (A): IC50 = 200 nmol/L, h = 0.92, a = 0.79 (○) and IC50 = 140 nmol/L, h = 0.88, a = 0.39 (●) and Kir6.2-I296L/SUR1 (B): IC50 = 930 nmol/L, h = 1.5, a = 0.95 (○) and IC50 = 1,200 nmol/L, h = 0.98, a = 0.41 (●). C and D: Simulation of the dependence of high-affinity gliclazide block on PO in nucleotide-free solutions with a Monod-Wyman-Changeux model. C: Fractional block of KATP current, as a function of gliclazide concentration, for different values of PO. Currents are expressed relative to those in the absence of gliclazide. The lines are drawn to the following: (1 + F + E0) × (1 + [S]/Kd,O)4/ [(1 + F) × (1 + [S]/Kd,O)4 + E0 × (1 + [S]/Kd,C)4], where F = 0.16 is the equilibrium gating constant for the fast intraburst transitions (from maximal PO of 0.86 when E0 = 0), E0 = [1 − PO × (1 + F)] / PO is the equilibrium gating constant for the slow interburst transitions, [S] is the gliclazide concentration, and Kd,O = 70 nmol/L and Kd,C = 50 nmol/L are the dissociation constants for gliclazide binding to the open and closed states, respectively. D: Monod-Wyman-Changeux model for gliclazide-dependent gating of KATP channels used to derive the current traces in C. This model is the simplest mechanism of concerted gating, which has previously been shown to occur in KATP channels (48–50). KC, sulphonylurea binding constant for the closed state; KO, sulphonylurea binding constant for the open state; S, sulphonylurea; t, proportionality factor reflecting the change in the equilibrium gating constant E0 when sulphonylurea is bound to the channel (t = KO/KC).

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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