title: Mechanism of action of a novel human ether-a-go-go-related gene channel activator.
abstract: 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.
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute and Department of Physiology, University of Utah, Salt Lake City, 84112, USA.
authors.forename: Oscar
authors.initials: O
authors.lastname: Casis
authors.forename: Søren-Peter
authors.initials: SP
authors.lastname: Olesen
authors.forename: Michael C
authors.initials: MC
authors.lastname: Sanguinetti
mesh_terms: D000818:Animals; D001665:Binding Sites; D003408:Cresols / Q000494:pharmacology*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D009154:Mutation; D009865:Oocytes / Q000187:drug effects; D010671:Phenylurea Compounds / Q000494:pharmacology*; D014982:Xenopus laevis
chemical_list: D003408:Cresols; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010671:Phenylurea Compounds; C507624:1,3-bis(2-hydroxy-5-trifluoromethylphenyl)urea