Blockade of HERG Human K<sup>+</sup> Channels by the Antidepressant Drug Paroxetine

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  • Lee Seung Ho
    Department of Pharmacology, Institute for Medical Sciences, Chonbuk National University Medical School
  • Sung Min Ji
    Department of Pharmacology, Institute for Medical Sciences, Chonbuk National University Medical School
  • Lee Hyang Mi
    Department of Pharmacology, Institute for Medical Sciences, Chonbuk National University Medical School
  • Chu Daehyun
    Department of Physiology, Bio-Medical Institute of Technology, University of Ulsan College of Medicine
  • Hahn Sang June
    Department of Physiology, Bio-Medical Institute of Technology, University of Ulsan College of Medicine
  • Jo Su-Hyun
    Department of Physiology, Institute of Bioscience and Biotechnology, BK21 plus Graduate Program, Kangwon National University College of Medicine
  • Choe Han
    Department of Physiology, Bio-Medical Institute of Technology, University of Ulsan College of Medicine
  • Choi Bok Hee
    Department of Pharmacology, Institute for Medical Sciences, Chonbuk National University Medical School

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  • Highlighted Paper selected by Editor-in-Chief : Blockade of HERG Human K⁺ Channels by the Antidepressant Drug Paroxetine

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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.

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