Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine.

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Main MJ, Cryan JE, Dupere JR, Cox B, Clare JJ, Burbidge SA

Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine.

Mol Pharmacol. 2000 Aug;58(2):253-62.

PubMed ID

10908292 [ View in PubMed

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Abstract

Retigabine is a novel anticonvulsant with an unknown mechanism of action. It has recently been reported that retigabine modulates a potassium channel current in nerve growth factor-differentiated PC12 cells (), however, to date the molecular correlate of this current has not been identified. In the present study we have examined the effects of retigabine on recombinant human KCNQ2 and KCNQ3 potassium channels, expressed either alone or in combination in Xenopus oocytes. Application of 10 microM retigabine to oocytes expressing the KCNQ2/3 heteromeric channel shifted both the activation threshold and voltage for half-activation by approximately 20 mV in the hyperpolarizing direction, leading to an increase in current amplitude at test potentials between -80 mV and +20 mV. Retigabine also had a marked effect on KCNQ current kinetics, increasing the rate of channel activation but slowing deactivation at a given test potential. Similar effects of retigabine were observed in oocytes expressing KCNQ2 alone, suggesting that KCNQ2 may be the molecular target of retigabine. Membrane potential recordings in oocytes expressing the KCNQ2/3 heteromeric channel showed that application of retigabine leads to a concentration-dependent hyperpolarization of the oocyte, from a resting potential of -63 mV under control conditions to -85 mV in the presence of 100 microM retigabine (IC(50) = 5.2 microM). In control experiments retigabine had no effect on either resting membrane potential or endogenous oocyte membrane currents. In conclusion, we have shown that retigabine acts as a KCNQ potassium channel opener. Because the heteromeric KCNQ2/3 channel has recently been reported to underlie the M-current, it is likely that M-current modulation can explain the anticonvulsant actions of retigabine in animal models of epilepsy.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Ezogabine	Potassium voltage-gated channel subfamily KQT member 2	Protein	Humans	Unknown	Not Available	Details
Ezogabine	Potassium voltage-gated channel subfamily KQT member 3	Protein	Humans	Unknown	Not Available	Details

Polypeptides

Name	UniProt ID
Potassium voltage-gated channel subfamily KQT member 2	O43526	Details
Potassium voltage-gated channel subfamily KQT member 3	O43525	Details