The molecular determinants of R-roscovitine block of hERG channels
Fig 8
R-roscovitine inhibition is almost completely abolished in F656A hERG.
A) Voltage protocol and representative current traces of a cell expressing F656A before (Control) and during 500 μM R-roscovitine application. B) F656A tail I-V curves during the step repolarization protocol (currents measured at ◊). Quadratic fits generated to obtain Erev values (Ctrl = -45.1 ± 1.1 mV, Rosc = -42.1 ± 1.7 mV) did in fact show a shift with drug block (p = 0.02, n = 9, paired t-test). C) F656A tail current inhibition was almost non-existent for most repolarized voltages, which was a substantial difference from WT inhibition (p < 0.01 for WT vs. F656A between +20 mV and -120 mV (excluding points close to the reversal potential), nWT = 10, nF656A = 9, one-way ANOVA). D) Concentration-response relationship for F656A hERG IC50 (21.5 ± 10.6 mM) shows a ~ 42-fold increase from WT IC50 (513 ± 43 μM; p = 0.0004); and a significant reduction in the slope of the Hill equation from 1.1 ± 0.22 for WT to 0.42 ± 0.04 for F656; p < 0.005; nWT = 9, nF656A = 5, Kruskal-Wallis tests. ** = P < 0.01, and *** = P < 0.001.