Abstract
Acquired long QT syndrome is most often caused by block of cardiac HERG K+ channels by commonly used medications. We determined the structural basis for high-affinity block of HERG channels by class III antiarrhythmic agents, including dofetilide, E-4031, MS-551, amiodarone, dronedarone and bepridil. We mutated to alanine individual residues of the S6 transmembrane domain (L646-Y667) and the few residues of the pore helix (L622-V625) predicted to line the inner channel cavity based on homology with the solved crystal structure of the KcsA channel. Block of each mutant channel expressed in Xenopus oocytes was determined using a concentration of drug equal to 10-times the IC50 value (2.2 μM dofetilide, 5.7 μM E-4031, 58 μM MS-551, 18 μM amiodarone, 28 μM drondedarone and 30 μM bepridil). Currents were measured during repetitive 5-s depolarizing steps to 0 mV, applied at 0.166 Hz. At these concentrations, each drug caused ~ 85% inhibition of wild-type HERG current and most mutant channels. Block of HERG current by dofetilide, E-4031 and MS-551 was less for 3 pore helix mutants (T623A, S624A and V625A) and 3 S6 domain mutants (G648A, F656A and V659A). Y652A and F656A mutation in the S6 domain and the mutations in the pore helix reduced block by most drugs. These results confirm that residues in the S6 domain and base of the pore helix form the drug binding site on the HERG channel, and the central importance of F656 and Y652. [Jpn J Physiol 54 Suppl:S253 (2004)]
