title: Voltage-independent KCNQ4 currents induced by (+/-)BMS-204352.
abstract: The compound BMS-204352 has been targeted for use against acute ischemic stroke, due to its activation of the large-conductance Ca2+-activated K-channel (BK). We have previously described that the racemate (+/-)BMS-204352 reversibly modulates KCNQ4 voltage dependency. Here we show that (+/-)BMS-204352 also induces a voltage-independent KCNQ4 current. The channels were stably expressed in human embryonic kidney cells (HEK293), and investigated by use of the whole-cell mode of the patch-clamp technique. (+/-)BMS-204352 was applied extracellularly (10 microM) in order to precipitate the robust appearance of the voltage-independent current. The voltage-independent KCNQ4 currents were recorded as instantaneous increases in currents upon hyperpolarizing or depolarizing voltage steps elicited from holding potentials of -90 or -110 mV. The voltage-independent current reversed at the equilibrium potential for potassium ( E(K)), hence was carried by a K+ conductance, and was blocked by the selective KCNQ channel blockers XE991 and linopirdine. Similar results were obtained with KCNQ4 channels transiently transfected into Chinese hamster ovary cells (CHO). When (+/-)BMS-204352 was applied to stably expressed BK channels, only the voltage dependency was modulated. Retigabine, the classic activator of KCNQ channels, did not induce voltage-independent currents. Our data indicate that KCNQ4 channels may conduct voltage-dependent and voltage-independent currents in the presence of (+/-)BMS-204352.
authors.affiliation: NeuroSearch A/S, 93 Pederstrupvej, DK 2750 Ballerup, Denmark.
authors.forename: Rikke Louise
authors.initials: RL
authors.lastname: Schrøder
authors.forename: Dorte
authors.initials: D
authors.lastname: Strøbaek
authors.forename: Søren-Peter
authors.initials: SP
authors.lastname: Olesen
authors.forename: Palle
authors.initials: P
authors.lastname: Christophersen
mesh_terms: D000818:Animals; D016466:CHO Cells; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D006224:Cricetinae; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D051656:KCNQ Potassium Channels; D007668:Kidney / Q000166:cytology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated
chemical_list: C424388:BMS204352; D002120:Calcium Channel Agonists; D007211:Indoles; D051656:KCNQ Potassium Channels; C117367:KCNQ4 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated