title: Blockade of HERG human K+ channels by the antidepressant drug paroxetine.
abstract: The effects of paroxetine, a selective serotonin reuptake inhibitor, on human ether-a-go-go-related gene (HERG) channels were investigated using the whole-cell patch-clamp technique. The HERG channels were stably expressed in human embryonic kidney cells. Paroxetine inhibited the peak tail currents of the HERG channel in a concentration-dependent manner, with an IC50 value of 0.45 µM and a Hill coefficient of 0.85. These effects were reversible after wash-out of the drug. The paroxetine-induced inhibition of the HERG channels was voltage-dependent. There was a steep increase in inhibition over the voltage range of the channel opening. Also, a shallow voltage-dependent inhibition was detected over the voltage range in which the channels were fully activated. The fractional electrical distance was estimated to be 0.11. Paroxetine induced a leftward shift in the voltage-dependence of the steady-state activation of the HERG channels. Before and after application of the 1 µM paroxetine, the half-maximum activation was -14.21 mV and -27.04 mV, respectively, with no shift in the slope value. The HERG channel block was not use-dependent. The characteristics of the block were dependent on open and inactivated channel states rather than closed state. Paroxetine had no effect on activation and deactivation kinetics, steady-state inactivation. These results suggest that paroxetine blocks the HERG channels by binding to these channels in the open and inactivated states.
authors.affiliation: Department of Pharmacology, Institute for Medical Sciences, Chonbuk National University Medical School.
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Min Ji
authors.initials: MJ
authors.lastname: Sung
authors.forename: Hyang Mi
authors.initials: HM
authors.lastname: Lee
authors.forename: Daehyun
authors.initials: D
authors.lastname: Chu
authors.forename: Sang June
authors.initials: SJ
authors.lastname: Hahn
authors.forename: Su-Hyun
authors.initials: SH
authors.lastname: Jo
authors.forename: Han
authors.initials: H
authors.lastname: Choe
authors.forename: Bok Hee
authors.initials: BH
authors.lastname: Choi
mesh_terms: D000928:Antidepressive Agents / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008958:Models, Molecular; D017374:Paroxetine / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D051638:Ether-A-Go-Go Potassium Channels; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors