title: The acrylamide (S)-1 differentially affects Kv7 (KCNQ) potassium channels.
abstract: The family of Kv7 (KCNQ) potassium channels consists of five members. Kv7.2 and 3 are the primary molecular correlates of the M-current, but also Kv7.4 and Kv7.5 display M-current characteristics. M-channel modulators include blockers (e.g., linopirdine) for cognition enhancement and openers (e.g., retigabine) for treatment of epilepsy and neuropathic pain. We investigated the effect of a Bristol-Myers Squibb compound (S)-N-[1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl-acrylamide [(S)-1] on cloned human Kv7.1-5 potassium channels expressed in Xenopus laevis oocytes. Using two-electrode voltage-clamp recordings we found that (S)-1 blocks Kv7.1 and Kv7.1/KCNE1 currents. In contrast, (S)-1 produced a hyperpolarizing shift of the activation curve for Kv7.2, Kv7.2/Kv7.3, Kv7.4 and Kv7.5. Further, the compound enhanced the maximal current amplitude at all potentials for Kv7.4 and Kv7.5 whereas the combined activation/block of Kv7.2 and Kv7.2/3 was strongly voltage-dependent. The tryptophan residue 242 in S5, known to be crucial for the effect of retigabine, was also shown to be critical for the enhancing effect of (S)-1 and BMS204352. Furthermore, no additive effect on Kv7.4 current amplitude was observed when both retigabine and (S)-1 or BMS204352 were applied simultaneously. In conclusion, (S)-1 differentially affects the Kv7 channel subtypes and is dependent on a single tryptophan for the current enhancing effect in Kv7.4.
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia and Department of Medical Physiology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
authors.forename: Bo Hjorth
authors.initials: BH
authors.lastname: Bentzen
authors.forename: Nicole
authors.initials: N
authors.lastname: Schmitt
authors.forename: Kirstine
authors.initials: K
authors.lastname: Calloe
authors.forename: William
authors.initials: W
authors.lastname: Dalby Brown
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.forename: Søren-Peter
authors.initials: SP
authors.lastname: Olesen
mesh_terms: D000178:Acrylamides / Q000378:metabolism / Q000494:pharmacology*; D000465:Algorithms; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004594:Electrophysiology; D006801:Humans; D051656:KCNQ Potassium Channels / Q000187:drug effects* / Q000235:genetics; D051657:KCNQ1 Potassium Channel / Q000187:drug effects; D051658:KCNQ2 Potassium Channel / Q000187:drug effects; D007700:Kinetics; D009025:Morpholines / Q000378:metabolism / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017354:Point Mutation / Q000187:drug effects; D014364:Tryptophan / Q000187:drug effects / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D000178:Acrylamides; D018076:DNA, Complementary; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D051658:KCNQ2 Potassium Channel; C117367:KCNQ4 protein, human; D009025:Morpholines; C476437:N-(1-(3-morpholin-4-ylphenyl)ethyl)-3-phenylacrylamide; D014364:Tryptophan