| Title | Drug binding to the inactivated state is necessary but not sufficient for high affinity binding to hERG channels. | | Author(s) | Perrin MJ, Kuchel PW, Campbell TJ, Vandenberg JI | | Institution | St Vincent's Clinical School (University of New South Wales). | | Source | Mol Pharmacol 2008 Aug 13. | | Abstract | Drug block of the human ether a-go-go related gene K(+) channel (hERG) is the most common cause of acquired long QT syndrome, a disorder of cardiac repolarization that may result in ventricular tachycardia and sudden cardiac death. We investigated the open versus inactivated state dependence of drug block by utilizing hERG mutants N588K and N588E, that shift the voltage dependence of inactivation compared to wild-type but where the mutated residue is remote from the drug-binding pocket in the channel pore. Four high affinity drugs (cisapride, dofetilide, terfenadine, astemizole) demonstrated lower affinity for the inactivation-deficient N588K mutant hERG channel compared with N588E and wild type hERG. Three of four low affinity drugs (erythromycin, perhexiline, and quinidine) demonstrated no preference for N588E over N588K channels, while dl-sotalol was an example of a low-affinity state-dependent blocker. All five state-dependent blockers showed an even lower affinity for S620T mutant hERG (no inactivation) compared with N588K mutant hERG (greatly reduced inactivation). Computer modeling indicates that the reduced affinity for S620T compared to N588K and wild type channels can be explained by the relative kinetics of drug block and unblock compared to the kinetics of inactivation and recovery from inactivation. We were also able to calculate, for the first time, the relative affinities for the inactivated versus the open state, which for the drugs tested here ranged from 4-70 fold. Our results show that preferential binding to the inactivated state is necessary but not sufficient for high affinity binding to hERG channels. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 18701618 |
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