Characterization of A-935142, a hERG enhancer, in the presence and absence of standard hERG blockers

Abstract

AimsIn a previous study we found that A-935142 enhanced hERG current in a concentration-dependent manner by facilitating activation, reducing inactivation, and slowing deactivation (Su et al., 2009). A-935142 also shortened action potential duration (APD90) in canine Purkinje fibers and guinea pig atrial tissue. This study focused on the combined effects of the prototypical hERG enhancer, A-935142 and two hERG current blockers (sotalol and terfenadine). Main methodsThe whole-cell voltage clamp method with HEK 293 cells heterologously expressing the hERG channel (Kv 11.1) was used. Key findingsA-935142 did not compete with 3H-dofetilide binding, suggesting that A-935142 does not overlap the binding site of typical hERG blockers. In whole-cell voltage clamp studies we found: 1) 60μM A-935142 enhanced hERG current in the presence of 150μM sotalol (57.5±5.8%) to a similar extent as seen with A-935142 alone (55.6±5.1%); 2) 150μM sotalol blocked hERG current in the presence of 60μM A-935142 (43.5±1.5%) to a similar extent as that seen with sotalol alone (42.0±3.2%) and 3) during co-application, hERG current enhancement was followed by current blockade. Similar results were obtained with 60nM terfenadine combined with A-935142. SignificanceThese results suggest that the hERG enhancer, A-935142 does not compete with these two known hERG blockers at their binding site within the hERG channel. This selective hERG current enhancement may be useful as a treatment for inherited or acquired LQTS (Casis et al., 2006).