화학공학소재연구정보센터
Biochemical and Biophysical Research Communications, Vol.351, No.1, 273-280, 2006
HERG K+ channel blockade by the antipsychotic drug thioridazine: An obligatory role for the S6 helix residue F656
The phenothiazine antipsychotic agent thioridazine has been linked with prolongation of the QT interval on the electrocardiogram, ventricular arrhythmias, and sudden death. Although thioridazine is known to inhibit cardiac hERG K+ channels there is little mechanistic information on this action. We have investigated in detail hERG K+ channel current (I-hERG) blockade by thioridazine and identified a key molecular determinant of blockade. Whole-cell IhERG measurements were made at 37 C from human embryonic kidney (HEK-293) cells expressing wild-type and mutant hERG channels. Thioridazine inhibited I-hERG tails at -40 mV following a 2 s depolarization to +20 mV with an IC50 value of 80 nM. Comparable levels of I-hERG inhibition were seen with physiological command waveforms (ventricular and Purkinje fibre action potentials). Thioridazine block of I-hERG was only weakly voltage-dependent, though the time dependence of IhERG inhibition indicated contingency of blockade upon channel gating. The S6 helix point mutation F656A almost completely abolished, and the Y652A mutation partially attenuated, I-hERG inhibition by thioridazine. In summary, thioridazine is one of the most potent hERG K+ channel blockers amongst antipsychotics, exhibiting characteristics of a preferential open/activated channel blocker and binding at a high affinity site in the hERG channel pore. (c) 2006 Elsevier Inc. All rights reserved.