Clomipramine block of the hERG K+ channel: accessibility to F656 and Y652.
Clomipramine is a tricyclic antidepressant for psychiatric disorders that can induce QT prolongation, which may lead to torsades de pointes. Since blockade of cardiac human ether-a-go-go-related gene (hERG) channels is an important cause of acquired long QT syndrome, we investigated the acute effects of clomipramine on hERG channels to determine the electrophysiological basis for its proarrhythmic potential. We examined the effects of clomipramine on the hERG channels expressed in Xenopus oocytes and HEK293 cells using two-microelectrode voltage-clamp and patch-clamp techniques. Clomipramine induced a concentration-dependent decrease in the current amplitude at the end of the voltage steps and hERG tail currents. The IC50 for clomipramine needed to block the hERG current in Xenopus oocytes decreased progressively relative to the degree of depolarization. The fractional electrical distance was estimated to be delta=0.83. The IC50 for the clomipramine-induced blockade of the hERG currents in HEK293 cells at 36 degrees C was 0.13 microM at +20 mV. Clomipramine affected the channels in the activated and inactivated states but not in the closed states. The clomipramine-induced blockade of hERG was found to be use-dependent, exhibiting a more rapid onset and a greater steady-state block at the higher frequencies of activation. The S6 domain mutations, Y652A and F656A partially attenuated (Y652A) or abolished (F656A) the hERG-current blockade. These results suggest that clomipramine is a blocker of the hERG channels, providing a molecular mechanism for the arrhythmogenic side effects during the clinical administration of clomipramine.
Jo
Su-Hyun
SH
Department of Physiology, Institute of Bioscience and Biotechnology, Kangwon National University College of Medicine, Chuncheon 200-701, Korea. suhyunjo@kangwon.ac.kr
Hong
Hee-Kyung
HK
Chong
Seon Ha
SH
Won
Kwang Hee
KH
Jung
Sung Jun
SJ
Choe
Han
H
D000465:Algorithms; D000818:Animals; D002478:Cells, Cultured; D002997:Clomipramine / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017354:Point Mutation / Q000235:genetics / Q000502:physiology; D026902:Potassium Channel Blockers; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D014982:Xenopus laevis
D002997:Clomipramine; D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D017367:Selective Serotonin Reuptake Inhibitors