The rapid delayed rectifier K+ current (IKr) plays an important role in ventricular repolarisation in the mammalian heart. The pore-forming subunit of IKr is considered to be encoded by human ether-à-go-go-related gene (hERG)(Sanguinetti and Tristani-Firouzi, 2006). In vivo, functional IKr channels may involve other ancillary subunits (Abbott et al., 2007). KCNE1, a protein which is best known as the β-subunit of the slow delayed rectifier K+ current (IKs) , has been suggested to modify hERG channel function (McDonald et al., 1997). Diverse clinically-used drugs produce hERG channel blockade and lead to acquired long QT syndrome. There is some evidence that KCNE1 variants may influence hERG current (IhERG; eg.Ohno et al., 2007); however it is not known whether or not such variants may influence susceptibility to drug induced arrhythmias by influencing IhERG pharmacology. We have addressed this issue through experiments on recombinant hERG channels co-expressed with either wild-type (WT) KCNE1 or a variant (A8V) that has previously been reported to influence IhERG magnitude and be associated with a long QT phenotype (Ohno et al., 2007). Whole-cell patch-clamp measurements of IhERG were made at 37oC. Consistent with prior observations (McDonald et al., 1997), we found that expression of WT KCNE1 in hERG expressing cells produced a hyperpolarising shift in the voltage dependence of IhERG activation (V0.5 of -16.06 ± 0.97 mV for IhERG, n= 14 cells; and V0.5 of -26.94 ± 1.09 mV for IhERG-KCNE1, n= 9 cells). A similar shift was also seen for A8V KCNE1 variant (V0.5 of -26.40 ± 1.8 mV for A8V KCNE1, n= 9 cells, p>0.05 versus WT KCNE1). The amplitude of IhERG was smaller for A8V KCNE1 + hERG than for WT KCNE1 + hERG, under both conventional voltage clamp and “action potential” clamp (AP clamp; performed using a physiological ventricular AP waveform). Using paired AP commands, with the second AP waveform applied at varying time-intervals to mimic premature ventricular excitation, the response of IhERG carried by A8V KCNE1 + hERG was reduced in comparison to that of WT KCNE1 + hERG. The IhERG blocking potency of the Class I antiarrhythmic drug quinidine was similar between WT KCNE1 (IC50 of 0.54 ± 0.13 μM) and A8V KCNE1 (IC50 of 0.47 ± 0.11 μM). On the other hand, the IhERG inhibitory potency of the antibiotic clarithyromycin was reduced for the A8V KCNE1 variant (IC50 of 80.26 ± 9.2 μM) compared with WT KCNE1 (IC50 of 40.85 ± 4.39 μM). These results demonstrate that, in principle, the A8V KCNE1 variant may alter the protective response of hERG channels to premature excitatory stimuli and the sensitivity of hERG channels to inhibition by drugs linked to acquired long QT syndrome.