Mechanism of action of a novel human ether-a-go-go-related gene channel activator.
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Mechanism of action of a novel human ether-a-go-go-related gene channel activator. / Casis, Oscar; Olesen, Søren-Peter; Sanguinetti, Michael C.
In: Molecular Pharmacology, Vol. 69, No. 2, 2005, p. 658-65.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Mechanism of action of a novel human ether-a-go-go-related gene channel activator.
AU - Casis, Oscar
AU - Olesen, Søren-Peter
AU - Sanguinetti, Michael C
N1 - Keywords: Animals; Binding Sites; Cresols; Ether-A-Go-Go Potassium Channels; Humans; Mutation; Oocytes; Phenylurea Compounds; Xenopus laevis
PY - 2005
Y1 - 2005
N2 - 1,3-Bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643) is a newly discovered activator of human ether-a-go-go-related gene (hERG) K(+) channels. Here, we characterize the effects of this compound on cloned hERG channels heterologously expressed in Xenopus laevis oocytes. When assessed with 2-s depolarizations, NS1643 enhanced the magnitude of wild-type hERG current in a concentration- and voltage-dependent manner with an EC(50) of 10.4 microM at -10 mV. The fully activated current-voltage relationship revealed that the drug increased outward but not inward currents, consistent with altered inactivation gating. NS1643 shifted the voltage dependence of inactivation by +21 mV at 10 microM and +35 mV at 30 microM, but it did not alter the voltage dependence of activation of hERG channels. The effects of the drug on three inactivation-deficient hERG mutant channels (S620T, S631A, and G628C/S631C) were determined. In the absence of channel inactivation, NS1643 did not enhance hERG current magnitude. The agonist activity of NS1643 was facilitated by mutations (F656 to Val, Met, or Thr) that are known to greatly attenuate channel inhibition by hERG blockers. We conclude that NS1643 is a partial agonist of hERG channels and that the mechanism of activation is reduced channel inactivation.
AB - 1,3-Bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643) is a newly discovered activator of human ether-a-go-go-related gene (hERG) K(+) channels. Here, we characterize the effects of this compound on cloned hERG channels heterologously expressed in Xenopus laevis oocytes. When assessed with 2-s depolarizations, NS1643 enhanced the magnitude of wild-type hERG current in a concentration- and voltage-dependent manner with an EC(50) of 10.4 microM at -10 mV. The fully activated current-voltage relationship revealed that the drug increased outward but not inward currents, consistent with altered inactivation gating. NS1643 shifted the voltage dependence of inactivation by +21 mV at 10 microM and +35 mV at 30 microM, but it did not alter the voltage dependence of activation of hERG channels. The effects of the drug on three inactivation-deficient hERG mutant channels (S620T, S631A, and G628C/S631C) were determined. In the absence of channel inactivation, NS1643 did not enhance hERG current magnitude. The agonist activity of NS1643 was facilitated by mutations (F656 to Val, Met, or Thr) that are known to greatly attenuate channel inhibition by hERG blockers. We conclude that NS1643 is a partial agonist of hERG channels and that the mechanism of activation is reduced channel inactivation.
U2 - 10.1124/mol.105.019943
DO - 10.1124/mol.105.019943
M3 - Journal article
C2 - 16284303
VL - 69
SP - 658
EP - 665
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 2
ER -
ID: 8466445