The pharmacological effect of positive KCNQ (Kv7) modulators on dopamine release from striatal slices

TY - JOUR

T1 - The pharmacological effect of positive KCNQ (Kv7) modulators on dopamine release from striatal slices

AU - Jensen, Majbrit M

AU - Lange, Sofie Cecilie

AU - Thomsen, Morten Skøtt

AU - Hansen, Henrik H

AU - Mikkelsen, Jens D

N1 - © 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.

PY - 2011/11

Y1 - 2011/11

N2 - Retigabine is an anti-epileptic drug that inhibits neuronal firing by stabilizing the membrane potential through positive modulation of voltage-dependent KCNQ potassium channels in cortical neurons and in mesencephalic dopamine (DA) neurons. The purpose of this study was to compare the effect of retigabine with other positive KCNQ modulators on the KCl-induced release of DA in rat striatal slices. Retigabine was found to inhibit KCl-dependent release of DA, and the IC(50) was estimated to be 0.7 µM. The KCNQ channel blocker XE-991 enhanced striatal DA release and completely abolished the effect of retigabine. Other compounds of the same class but with some preferences for different KCNQ subtypes such as ICA-27243, BMS-204352 and S-(1) were also tested. All three compounds produced a significant effect albeit weaker than retigabine. The potency of ICA-27243 was in the range of retigabine, and with a lower potency of BMS-204352 and S-(1). This study demonstrates that KCNQ channel openers inhibit KCl-induced DA release at relevant concentrations. The equal potency of ICA-27243 and retigabine suggests that the KCNQ2/3 isoform is likely the dominant subtype mediating this effect.

AB - Retigabine is an anti-epileptic drug that inhibits neuronal firing by stabilizing the membrane potential through positive modulation of voltage-dependent KCNQ potassium channels in cortical neurons and in mesencephalic dopamine (DA) neurons. The purpose of this study was to compare the effect of retigabine with other positive KCNQ modulators on the KCl-induced release of DA in rat striatal slices. Retigabine was found to inhibit KCl-dependent release of DA, and the IC(50) was estimated to be 0.7 µM. The KCNQ channel blocker XE-991 enhanced striatal DA release and completely abolished the effect of retigabine. Other compounds of the same class but with some preferences for different KCNQ subtypes such as ICA-27243, BMS-204352 and S-(1) were also tested. All three compounds produced a significant effect albeit weaker than retigabine. The potency of ICA-27243 was in the range of retigabine, and with a lower potency of BMS-204352 and S-(1). This study demonstrates that KCNQ channel openers inhibit KCl-induced DA release at relevant concentrations. The equal potency of ICA-27243 and retigabine suggests that the KCNQ2/3 isoform is likely the dominant subtype mediating this effect.

U2 - 10.1111/j.1742-7843.2011.00730.x

DO - 10.1111/j.1742-7843.2011.00730.x

M3 - Journal article

C2 - 21599837

SN - 1742-7843

VL - 109

SP - 339

EP - 342

JO - Basic & Clinical Pharmacology & Toxicology Online

JF - Basic & Clinical Pharmacology & Toxicology Online

IS - 5

ER -