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

AIM: 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 (S631A).

CONCLUSION

The inactivation gating of HERG channels determines the blocking potency of drugs. This mechanism might be common to drugs of various classes.