Referenced in: none

Automatically associated channels: Kv11.1 , Kv4.1 , Slo1

Title: Blockade of HERG human K+ channels by the antidepressant drug paroxetine.

Authors: Seung Ho Lee, Min Ji Sung, Hyang Mi Lee, Daehyun Chu, Sang June Hahn, Su-Hyun Jo, Han Choe, Bok Hee Choi

Journal, date & volume: Biol. Pharm. Bull., 2014 , 37, 1495-504

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25177033

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.