Cardiac potassium channels have been described as the site of action of many drugs that cause fatal ventricular arrythmias. The hERG channel, in particular, has been shown to be targeted by a variety of drugs that cause drug-induced long QT syndrome and torsades de pointe. Recently it has been shown that hERG binds such drugs in its internal cavity at a site analogous to the quaternary ammonium (QA) site of KcsA. Consistent with the proposed location of hERG's drug-binding site, many known hERG blockers show voltage- and state-dependence that is reminiscent of QA blockade. The mechanism of voltage- and state-dependence of QA block is unknown, but we have recently suggested that it may arise as a result of a drug-permeant ion interaction that is itself voltage- and state-dependent. We hypothesize that voltage- and state-dependence of drug-binding to the hERG potassium channel arises as a result of energetic coupling between blocker and permeant ions. The proposed experiments utilize both structural and functional techniques to test our hypothesis.
