title: Effects of the small molecule HERG activator NS1643 on Kv11.3 channels.
abstract: NS1643 is one of the small molecule HERG (Kv11.1) channel activators and has also been found to increase erg2 (Kv11.2) currents. We now investigated whether NS1643 is also able to act as an activator of Kv11.3 (erg3) channels expressed in CHO cells. Activation of rat Kv11.3 current occurred in a dose-dependent manner and maximal current increasing effects were obtained with 10 µM NS1643. At this concentration, steady-state outward current increased by about 80% and the current increase was associated with a significant shift in the voltage dependence of activation to more negative potentials by about 15 mV. In addition, activation kinetics were accelerated, whereas deactivation was slowed. There was no significant effect on the kinetics of inactivation and recovery from inactivation. The strong current-activating agonistic effect of NS1643 did not result from a shift in the voltage dependence of Kv11.3 channel inactivation and was independent from external Na(+) or Ca(2+). At the higher concentration of 20 µM, NS1643 induced clearly less current increase. The left shift in the voltage dependence of activation reversed and the voltage sensitivity of activation dramatically decreased along with a slowing of Kv11.3 channel activation. These data show that, in comparison to other Kv11 family members, NS1643 exerts distinct effects on Kv11.3 channels with especially pronounced partial antagonistic effects at higher concentration.
authors.affiliation: Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Bilet
authors.forename: Christiane K
authors.initials: CK
authors.lastname: Bauer
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000494:pharmacology; D003408:Cresols / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects*; D007700:Kinetics; D010671:Phenylurea Compounds / Q000494:pharmacology*; D051381:Rats; D012964:Sodium / Q000494:pharmacology; D013997:Time Factors
chemical_list: D003408:Cresols; D051638:Ether-A-Go-Go Potassium Channels; C496886:Kcnh1 protein, rat; D010671:Phenylurea Compounds; C507624:1,3-bis(2-hydroxy-5-trifluoromethylphenyl)urea; D012964:Sodium; D002118:Calcium