Referenced in: none

Automatically associated channels: Kir2.3 , Kv11.1

Title: Frequency- and state-dependent blockade of human ether-a-go-go-related gene K+ channel by arecoline hydrobromide.

Authors: Xu-yan Zhao, Yu-qi Liu, Yi-cheng Fu, Bin Xu, Jin-liao Gao, Xiao-qin Zheng, Min Lin, Mei-yan Chen, Yang Li

Journal, date & volume: Chin. Med. J., 2012 Mar , 125, 1068-75

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/22613533

Abstract
The rapidly activating delayed rectifier potassium current (I(Kr)), whose pore-forming alpha subunit is encoded by the human ether-a-go-go-related gene (hERG), is a key contributor to the third phase of action potential repolarization. The aim of this study was to investigate the effect and mechanism of arecoline hydrobromide induced inhibition of hERG K(+) current (I(hERG)).Transient transfection of hERG channel cDNA plasmid pcDNA3.1 into the cultured HEK293 cells was performed using Lipofectamine. A standard whole-cell patch-clamp technique was used to record the I(hERG) before and after the exposure to arecoline.Arecoline decreased the amplitude and the density of the I(hERG) in a concentration-dependent manner (IC(50) = 9.55 mmol/L). At test potential of +60 mV, the magnitude of I(hERG) tail at test pulse of -40 mV was reduced from (151.7 ± 6.2) pA/pF to (84.4 ± 7.6) pA/pF (P < 0.01, n = 20) and the magnitude of I(hERG) tail at test pulse of -110 mV was reduced from (-187.5 ± 9.8) pA/pF to (-97.6 ± 12.6) pA/pF (P < 0.01, n = 20). The blockade of arecoline in the open and inactivated state was significant in a state-dependent manner. The maximal blockade was achieved in the inactivated state. Studies of gating mechanism showed that the steady-state activation curve of I(hERG) was significantly negatively shifted by arecoline. Time constants of activation were shortened. Steady-state inactivation curve and time constants of fast inactivation were not significantly affected by arecoline. Furthermore, the inhibition of I(hERG) by arecoline was characterized markedly by a frequency-dependent manner from 0.03 to 1.00 Hz pulse.Arecoline could potently block I(hERG) in both frequency and state-dependent manner.