Inactivation gating determines drug potency：a common mechanism for drug blockade of HERG channels

INTRODUCTIONThe K channel encoded by HERG (the humanether-a-go-go related gene) is well accepted as anequivalent of the native delayed rectifier K channel IKrin cardiac myocytes. Indeed, when expressed in eithermammalian cells or Xenopus oocytes, the HERG chan-nel current is virtually identical to IKr in terms of thebiophysical properties and pharmacological sensitivity.This channel provides a mechanistic link between theacquired and the inherited long Q-T syndrome[1]. Thepharm…

Inactivation gating determines drug potency: a common mechanism for drug blockade of HERG channels

To determine the mechanisms of interactions between different drugs and HERG channels. METHODS:Various antiarrhythmic (dofetilide, quinidine, azimilide, RP58866) and non-antiarrhythmic (terfenadine, nicotine)agents were used on HERG channels expressed in Xenopus oocyte. Whole-cell voltage-clamp techniques were used. RESULTS: All drugs produced concentration-dependent block of HERG current. The inhibition was markedly facilitated with voltage protocols favoring channel inactivation (eg, less negative holding potentials). Maneuvers that weakened channel inactivation (eg, elevation of external K~), relieved HERG blockade by all drugs. Moreover,the inhibitory potency was reduced by at least 20-300 fold with varying compounds when rapid C-type inactivation was removed by a mutation located between the transmembrane domains 5 and 6 ($631A). CONCLUSION: The inactivation gating of HERG channels determines the blocking potency of drugs. This mechanism might be common to drugs of various classes.