title: Biophysical characterization of KV3.1 potassium channel activating compounds.
abstract: The effect of two positive modulators, RE1 and EX15, on the voltage-gated K(+) channel Kv3.1 was investigated using the whole-cell patch-clamp technique on HEK293 cells expressing Kv3.1a. RE1 and EX15 increased the Kv3.1 currents in a concentration-dependent manner with an EC50 value of 4.5 and 1.3µM, respectively. However, high compound concentrations caused an inhibition of the Kv3.1 current. The compound-induced activation of Kv3.1 channels showed a profound hyperpolarized shift in activation kinetics. 30µM RE1 shifted V1/2 from 5.63±0.31mV to -9.71±1.00mV and 10µM EX15 induced a shift from 10.77±0.32mV to -15.11±1.57mV. The activation time constant (Tauact) was reduced for both RE1 and EX15, with RE1 being the fastest activator. The deactivation time constant (Taudeact) was also markedly reduced for both RE1 and EX15, with EX15 inducing the most prominent effect. Furthermore, subjected to depolarizing pulses at 30Hz, both compounds were showing a use-dependent effect resulting in a reduction of the compound-mediated effect. However, during these conditions, RE1- and EX15-modified current amplitudes still exceeded the control condition amplitudes by up to 200%. In summary, the present study introduces the first detailed biophysical characterization of two new Kv3.1 channel modifying compounds with different modulating properties.
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: bstaskin90@gmail.com.
authors.forename: Bahar
authors.initials: B
authors.lastname: Taskin
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: nadiavs@sund.ku.dk.
authors.forename: Nadia Lybøl
authors.initials: NL
authors.lastname: von Schoubye
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: mash@sund.ku.dk.
authors.forename: Majid
authors.initials: M
authors.lastname: Sheykhzade
authors.affiliation: Global Research, Synaptic Transmission, H. Lundbeck A/S, Valby, Denmark. Electronic address: JFB@lundbeck.com.
authors.forename: Jesper Frank
authors.initials: JF
authors.lastname: Bastlund
authors.affiliation: Global Research, Synaptic Transmission, H. Lundbeck A/S, Valby, Denmark. Electronic address: MGRU@lundbeck.com.
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: thojes@sund.ku.dk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jespersen
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D006827:Hydantoins / Q000494:pharmacology; D007700:Kinetics; D011725:Pyridines / Q000494:pharmacology; D051670:Shaw Potassium Channels / Q000819:agonists* / Q000502:physiology
chemical_list: C000606940:EX15 hydantoin compound; D006827:Hydantoins; D011725:Pyridines; C000606939:RE1 hydantoin compound; D051670:Shaw Potassium Channels
keywords: Fast-spiking interneurons; GABAergic interneurons; K(v)3.1 channel activator; Potassium channels