Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels.

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Wickenden AD, Yu W, Zou A, Jegla T, Wagoner PK

Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels.

Mol Pharmacol. 2000 Sep;58(3):591-600.

PubMed ID

10953053 [ View in PubMed

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Abstract

Retigabine [N-(2-amino-4-[fluorobenzylamino]-phenyl) carbamic acid; D-23129] is a novel anticonvulsant, unrelated to currently available antiepileptic agents, with activity in a broad range of seizure models. In the present study, we sought to determine whether retigabine could enhance current through M-like currents in PC12 cells and KCNQ2/Q3 K(+) channels expressed in Chinese hamster ovary cells (CHO-KCNQ2/Q3). In differentiated PC12 cells, retigabine enhanced a linopirdine-sensitive current. The effect of retigabine was associated with a slowing of M-like tail current deactivation in these cells. Retigabine (0.1 to 10 microM) induced a potassium current and hyperpolarized CHO cells expressing KCNQ2/Q3 cells but not in wild-type cells. Retigabine-induced currents in CHO-KCNQ2/Q3 cells were inhibited by 60.6 +/- 11% (n = 4) by the KCNQ2/Q3 blocker, linopirdine (10 microM), and 82.7 +/- 5.4% (n = 4) by BaCl(2) (10 mM). The mechanism by which retigabine enhanced KCNQ2/Q3 currents involved large, drug-induced, leftward shifts in the voltage dependence of channel activation (-33.1 +/- 2.6 mV, n = 4, by 10 microM retigabine). Retigabine shifted the voltage dependence of channel activation with an EC(50) value of 1.6 +/- 0.3 microM (slope factor was 1.2 +/- 0.1, n = 4 to 5 cells per concentration). Retigabine (0.1 to 10 microM) also slowed the rate of channel deactivation, predominantly by increasing the contribution of a slowly deactivating tail current component. Our findings identify KCNQ2/Q3 channels as a molecular target for retigabine and suggest that activation of KCNQ2/Q3 channels may be responsible for at least some of the anticonvulsant activity of this agent.

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