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Received for publication October 25, 2005.
Revised November 10, 2005.
Accepted for publication November 11, 2005.
NS1643 (1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea) is a newly discovered activator of hERG K+ channels. Here we characterize the effects of this compound on cloned hERG channels heterologously expressed in Xenopus 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 EC50 of 10.4 µM 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 µM and +35 mV at 30 µM, but 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.
Key words:
Ion channel regulation, Potassium, Antiarrhythmic drugs, Func. analysis receptor/ion channel mutants
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