Strong activation of ether-à-go-go-related gene 1 K+ channel isoforms by NS1643 in human embryonic kidney 293 and Chinese hamster ovary cells.
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Strong activation of ether-à-go-go-related gene 1 K+ channel isoforms by NS1643 in human embryonic kidney 293 and Chinese hamster ovary cells. / Schuster, Anna M.; Glassmeier, Günter; Bauer, Christiane K.
In: MOL PHARMACOL, Vol. 80, No. 5, 5, 2011, p. 930-942.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Strong activation of ether-à-go-go-related gene 1 K+ channel isoforms by NS1643 in human embryonic kidney 293 and Chinese hamster ovary cells.
AU - Schuster, Anna M.
AU - Glassmeier, Günter
AU - Bauer, Christiane K.
PY - 2011
Y1 - 2011
N2 - Two different mechanisms leading to increased current have been described for the small-molecule human ether-à-go-go-related gene (herg) activator NS1643 [1,3-bis-(2-hydroxy-5-trifluoromethylphenyl)-urea]. On herg1a channels expressed in Xenopus laevis oocytes, it mainly acts via attenuation of inactivation and for rat (r) erg1b channels expressed in human embryonic kidney (HEK)-293 cells, it strongly shifts the activation curve to the left. We now investigated the NS1643 effects on erg1b channels in more detail and performed comparative experiments with rat and human erg1a in different expression systems. Significant differences were observed between expression systems, but not between the rat and human isoform. In HEK-293 or Chinese hamster ovary (CHO) cells, activation of rat erg1b channels occurred in a dose-dependent manner with a maximum current increase of 300% obtained with 10 ?M NS1643. In contrast, the NS1643-induced strong leftward shift in the voltage dependence of activation further increased with higher drug concentration, needed more time to develop, and exhibited use dependence. Coexpression of KCNE1 or KCNE2 did not attenuate this NS1643 effect on erg1 channel activation and did thus not mimic the lower drug potency on this parameter observed in oocytes. NS1643 (10 ?M) slowed erg1b channel deactivation and recovery from inactivation without significant changes in activation and inactivation kinetics. With the exception of accelerated activation, NS1643 affected erg1a channels similarly, but the effect was less pronounced than in erg1b or erg1a/1b channels. It is noteworthy that rerg1b and herg1a inactivation estimated from fully activated current voltage relationships were unaltered in the continued presence of 10 ?M NS1643 in the mammalian expression systems, indicating qualitative differences from NS1643 effects in X. laevis oocytes.
AB - Two different mechanisms leading to increased current have been described for the small-molecule human ether-à-go-go-related gene (herg) activator NS1643 [1,3-bis-(2-hydroxy-5-trifluoromethylphenyl)-urea]. On herg1a channels expressed in Xenopus laevis oocytes, it mainly acts via attenuation of inactivation and for rat (r) erg1b channels expressed in human embryonic kidney (HEK)-293 cells, it strongly shifts the activation curve to the left. We now investigated the NS1643 effects on erg1b channels in more detail and performed comparative experiments with rat and human erg1a in different expression systems. Significant differences were observed between expression systems, but not between the rat and human isoform. In HEK-293 or Chinese hamster ovary (CHO) cells, activation of rat erg1b channels occurred in a dose-dependent manner with a maximum current increase of 300% obtained with 10 ?M NS1643. In contrast, the NS1643-induced strong leftward shift in the voltage dependence of activation further increased with higher drug concentration, needed more time to develop, and exhibited use dependence. Coexpression of KCNE1 or KCNE2 did not attenuate this NS1643 effect on erg1 channel activation and did thus not mimic the lower drug potency on this parameter observed in oocytes. NS1643 (10 ?M) slowed erg1b channel deactivation and recovery from inactivation without significant changes in activation and inactivation kinetics. With the exception of accelerated activation, NS1643 affected erg1a channels similarly, but the effect was less pronounced than in erg1b or erg1a/1b channels. It is noteworthy that rerg1b and herg1a inactivation estimated from fully activated current voltage relationships were unaltered in the continued presence of 10 ?M NS1643 in the mammalian expression systems, indicating qualitative differences from NS1643 effects in X. laevis oocytes.
KW - Animals
KW - Humans
KW - CHO Cells
KW - Cricetinae
KW - Cricetulus
KW - Cell Line
KW - Cresols/pharmacology
KW - Ether-A-Go-Go Potassium Channels/genetics/metabolism
KW - Phenylurea Compounds/pharmacology
KW - Protein Isoforms/genetics/metabolism
KW - Xenopus laevis
KW - Animals
KW - Humans
KW - CHO Cells
KW - Cricetinae
KW - Cricetulus
KW - Cell Line
KW - Cresols/pharmacology
KW - Ether-A-Go-Go Potassium Channels/genetics/metabolism
KW - Phenylurea Compounds/pharmacology
KW - Protein Isoforms/genetics/metabolism
KW - Xenopus laevis
M3 - SCORING: Journal article
VL - 80
SP - 930
EP - 942
JO - MOL PHARMACOL
JF - MOL PHARMACOL
SN - 0026-895X
IS - 5
M1 - 5
ER -