Kv3.1/Kv3.2 channel positive modulators enable faster activating kinetics and increase firing frequency in fast-spiking GABAergic interneurons

Kim Boddum; Charlotte Hougaard; Julie Xiao-Ying Lin; Nadia Lybøl von Schoubye; Henrik Sindal Jensen; Morten Grunnet; Thomas Jespersen

doi:10.1016/j.neuropharm.2017.02.024

K_v3.1/K_v3.2 channel positive modulators enable faster activating kinetics and increase firing frequency in fast-spiking GABAergic interneurons

Kim Boddum^*, Charlotte Hougaard, Julie Xiao-Ying Lin, Nadia Lybøl von Schoubye, Henrik Sindal Jensen, Morten Grunnet, Thomas Jespersen

^*Corresponding author for this work

17 Citations (Scopus)

63 Downloads (Pure)

Abstract

Due to their fast kinetic properties, K_v3.1 voltage gated potassium channels are important in setting and controlling firing frequency in neurons and pivotal in generating high frequency firing of interneurons. Pharmacological activation of K_v3.1 channels may possess therapeutic potential for treatment of epilepsy, hearing disorders, schizophrenia and cognitive impairments. Here we thoroughly investigate the selectivity and positive modulation of the two small molecules, EX15 and RE01, on K_v3 channels. Selectivity studies, conducted in Xenopus laevis oocytes confirmed a positive modulatory effect of the two compounds on K_v3.1 and to a minor extent on K_v3.2 channels. RE01 had no effect on the K_v3.3 and K_v3.4 channels, whereas EX15 had an inhibitory impact on the K_v3.4 mediated current. Voltage-clamp experiments in monoclonal hK_v3.1b/HEK293 cells (34 °C) revealed that the two compounds indeed induced larger currents and faster activation kinetics. They also decrease the speed of deactivation and shifted the voltage dependence of activation, to a more negative activation threshold. Application of action potential clamping and repetitive stimulation protocols of hK_v3.1b expressing HEK293 cells revealed that EX15 and RE01 significantly increased peak amplitude, half width and decay time of K_v3.1 mediated currents, even during high-frequency action potential clamping (250 Hz). In rat hippocampal slices, EX15 and RE01 increased neuronal excitability in fast-spiking interneurons in dentate gyrus. Action potential frequency was prominently increased at minor depolarizing steps, whereas more marginal effects of EX15 and RE01 were observed after stronger depolarizations. In conclusion, our results suggest that EX15 and RE01 positive modulation of K_v3.1 and K_v3.2 currents facilitate increased firing frequency in fast-spiking GABAergic interneurons.

Original language	English
Journal	Neuropharmacology
Volume	118
Pages (from-to)	102-112
Number of pages	11
ISSN	0028-3908
DOIs	https://doi.org/10.1016/j.neuropharm.2017.02.024
Publication status	Published - 2017

Keywords

Fast-spiking interneuron
Hippocampus
K3 channel
Positive modulator
Selectivity profile

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Kv3.1/Kv3.2 channel positive modulators enable faster activating kinetics and increase firing frequency in fast-spiking GABAergic interneuronsFinal published version, 1.93 MBLicence: CC BY

Cite this

@article{93e1c82fa18042ec84e027ed2ee131b9,

title = "Kv3.1/Kv3.2 channel positive modulators enable faster activating kinetics and increase firing frequency in fast-spiking GABAergic interneurons",

abstract = "Due to their fast kinetic properties, Kv3.1 voltage gated potassium channels are important in setting and controlling firing frequency in neurons and pivotal in generating high frequency firing of interneurons. Pharmacological activation of Kv3.1 channels may possess therapeutic potential for treatment of epilepsy, hearing disorders, schizophrenia and cognitive impairments. Here we thoroughly investigate the selectivity and positive modulation of the two small molecules, EX15 and RE01, on Kv3 channels. Selectivity studies, conducted in Xenopus laevis oocytes confirmed a positive modulatory effect of the two compounds on Kv3.1 and to a minor extent on Kv3.2 channels. RE01 had no effect on the Kv3.3 and Kv3.4 channels, whereas EX15 had an inhibitory impact on the Kv3.4 mediated current. Voltage-clamp experiments in monoclonal hKv3.1b/HEK293 cells (34 °C) revealed that the two compounds indeed induced larger currents and faster activation kinetics. They also decrease the speed of deactivation and shifted the voltage dependence of activation, to a more negative activation threshold. Application of action potential clamping and repetitive stimulation protocols of hKv3.1b expressing HEK293 cells revealed that EX15 and RE01 significantly increased peak amplitude, half width and decay time of Kv3.1 mediated currents, even during high-frequency action potential clamping (250 Hz). In rat hippocampal slices, EX15 and RE01 increased neuronal excitability in fast-spiking interneurons in dentate gyrus. Action potential frequency was prominently increased at minor depolarizing steps, whereas more marginal effects of EX15 and RE01 were observed after stronger depolarizations. In conclusion, our results suggest that EX15 and RE01 positive modulation of Kv3.1 and Kv3.2 currents facilitate increased firing frequency in fast-spiking GABAergic interneurons.",

keywords = "Fast-spiking interneuron, Hippocampus, K3 channel, Positive modulator, Selectivity profile",

author = "Kim Boddum and Charlotte Hougaard and {Xiao-Ying Lin}, Julie and {von Schoubye}, {Nadia Lyb{\o}l} and Jensen, {Henrik Sindal} and Morten Grunnet and Thomas Jespersen",

year = "2017",

doi = "10.1016/j.neuropharm.2017.02.024",

language = "English",

volume = "118",

pages = "102--112",

journal = "Neuropharmacology",

issn = "0028-3908",

publisher = "Pergamon Press",

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TY - JOUR

T1 - Kv3.1/Kv3.2 channel positive modulators enable faster activating kinetics and increase firing frequency in fast-spiking GABAergic interneurons

AU - Boddum, Kim

AU - Hougaard, Charlotte

AU - Xiao-Ying Lin, Julie

AU - von Schoubye, Nadia Lybøl

AU - Jensen, Henrik Sindal

AU - Grunnet, Morten

AU - Jespersen, Thomas

PY - 2017

Y1 - 2017

N2 - Due to their fast kinetic properties, Kv3.1 voltage gated potassium channels are important in setting and controlling firing frequency in neurons and pivotal in generating high frequency firing of interneurons. Pharmacological activation of Kv3.1 channels may possess therapeutic potential for treatment of epilepsy, hearing disorders, schizophrenia and cognitive impairments. Here we thoroughly investigate the selectivity and positive modulation of the two small molecules, EX15 and RE01, on Kv3 channels. Selectivity studies, conducted in Xenopus laevis oocytes confirmed a positive modulatory effect of the two compounds on Kv3.1 and to a minor extent on Kv3.2 channels. RE01 had no effect on the Kv3.3 and Kv3.4 channels, whereas EX15 had an inhibitory impact on the Kv3.4 mediated current. Voltage-clamp experiments in monoclonal hKv3.1b/HEK293 cells (34 °C) revealed that the two compounds indeed induced larger currents and faster activation kinetics. They also decrease the speed of deactivation and shifted the voltage dependence of activation, to a more negative activation threshold. Application of action potential clamping and repetitive stimulation protocols of hKv3.1b expressing HEK293 cells revealed that EX15 and RE01 significantly increased peak amplitude, half width and decay time of Kv3.1 mediated currents, even during high-frequency action potential clamping (250 Hz). In rat hippocampal slices, EX15 and RE01 increased neuronal excitability in fast-spiking interneurons in dentate gyrus. Action potential frequency was prominently increased at minor depolarizing steps, whereas more marginal effects of EX15 and RE01 were observed after stronger depolarizations. In conclusion, our results suggest that EX15 and RE01 positive modulation of Kv3.1 and Kv3.2 currents facilitate increased firing frequency in fast-spiking GABAergic interneurons.

AB - Due to their fast kinetic properties, Kv3.1 voltage gated potassium channels are important in setting and controlling firing frequency in neurons and pivotal in generating high frequency firing of interneurons. Pharmacological activation of Kv3.1 channels may possess therapeutic potential for treatment of epilepsy, hearing disorders, schizophrenia and cognitive impairments. Here we thoroughly investigate the selectivity and positive modulation of the two small molecules, EX15 and RE01, on Kv3 channels. Selectivity studies, conducted in Xenopus laevis oocytes confirmed a positive modulatory effect of the two compounds on Kv3.1 and to a minor extent on Kv3.2 channels. RE01 had no effect on the Kv3.3 and Kv3.4 channels, whereas EX15 had an inhibitory impact on the Kv3.4 mediated current. Voltage-clamp experiments in monoclonal hKv3.1b/HEK293 cells (34 °C) revealed that the two compounds indeed induced larger currents and faster activation kinetics. They also decrease the speed of deactivation and shifted the voltage dependence of activation, to a more negative activation threshold. Application of action potential clamping and repetitive stimulation protocols of hKv3.1b expressing HEK293 cells revealed that EX15 and RE01 significantly increased peak amplitude, half width and decay time of Kv3.1 mediated currents, even during high-frequency action potential clamping (250 Hz). In rat hippocampal slices, EX15 and RE01 increased neuronal excitability in fast-spiking interneurons in dentate gyrus. Action potential frequency was prominently increased at minor depolarizing steps, whereas more marginal effects of EX15 and RE01 were observed after stronger depolarizations. In conclusion, our results suggest that EX15 and RE01 positive modulation of Kv3.1 and Kv3.2 currents facilitate increased firing frequency in fast-spiking GABAergic interneurons.

KW - Fast-spiking interneuron

KW - Hippocampus

KW - K3 channel

KW - Positive modulator

KW - Selectivity profile

U2 - 10.1016/j.neuropharm.2017.02.024

DO - 10.1016/j.neuropharm.2017.02.024

M3 - Journal article

C2 - 28242439

AN - SCOPUS:85015778777

SN - 0028-3908

VL - 118

SP - 102

EP - 112

JO - Neuropharmacology

JF - Neuropharmacology

ER -