Fig. 2
Conventional voltage and action potential (AP) clamp combined with biophysical AP modelling. a Shows families of hERG currents (IhERG; upper panels) elicited by a series of depolarising voltage commands to a range of test potentials (lower panels) under conventional voltage clamp. Numbers next to ionic current records denote voltage command potential. Left hand side shows WT IhERG data, whilst right hand side shows data for co-expression of WT channel with a loss-of-function variant (T634S [82]). Currents under the two conditions are shown on the same scale, indicating a marked loss-of-function effect of the missense mutation studied. b Shows profile of WT IhERG compared with that of WT + Variant (T634S, as per a) IhERG, elicited by a ventricular AP command (shown superimposed over current records). The plotted currents show mean ± SEM data from 5 experiments under each condition. The method allows direct visualization of the effect of this variant – producing a reduction in current throughout the AP plateau and repolarisation phase. c Shows the consequences of incorporation of the T634S hERG variant effect on ventricular AP repolarisation, using a human ventricular AP model. IKr was scaled to reflect the extent of current reduction found in voltage clamp experiments to mimic heterozygous variant expression conditions. This led to delayed repolarisation and AP prolongation. For further details see [82]