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Acta Pharmacol Sin. May 1, 2004; 25 (5): 554-60.

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

Yang BF , Xu DH , Xu CQ , Li Z , Du ZM , Wang HZ , Dong DL .

To determine the mechanisms of interactions between different drugs and HERG channels.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.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).The inactivation gating of HERG channels determines the blocking potency of drugs. This mechanism might be common to drugs of various classes.

PubMed ID: 15132818
Article link:

Genes referenced: kcnh2

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