The anticonvulsant retigabine is a subtype selective modulator of GABAA receptors

Within its range of therapeutic plasma concentrations, the anticonvulsant retigabine (ezogabine) is believed to selectively act on Kv7 channels. Here, the contribution of specific γ-aminobutyric acid (GABA)A receptor subtypes to the antiseizure effects of retigabine was investigated.

Using patch-clamp recordings, seizure-like activity, tonic currents, and GABA-induced currents in hippocampal neurons were tested for their sensitivity toward retigabine, as were recombinant GABAA receptors expressed in tsA 201 cells.

Retigabine reduced seizure-like activity elicited by low Mg(2+) in a concentration-dependent manner with half maximal inhibition at 1 microm. Seizure-like activity triggered by blocking either Kv7 channels or GABAA receptors was equally reduced by retigabine, but when these channels/receptors were blocked simultaneously, the inhibition was lost. Retigabine (10 microm) enhanced bicuculline-sensitive tonic currents in hippocampal neurons, but failed to affect GABA-evoked currents. However, when receptors involved in phasic GABAergic inhibition were blocked by penicillin, retigabine did enhance GABA-evoked currents. In tsA 201 cells expressing various combinations of GABAA receptor subunits, 10 microm retigabine enhanced currents through α1β2δ, α4β2δ, α4β3δ, and α6β2δ receptors, but left currents through α1β2γ2S, α4β3γ2S, α5β3γ2S, and α6β2γ2S receptors unaltered. With αβ receptors, retigabine diminished currents through α1β2 and α4β3, but increased currents through α6β2 receptors. The enhancement of currents through α1β2δ receptors by retigabine was concentration dependent and became significant at 1 microm.

These results demonstrate that retigabine is a subtype selective modulator of GABAA receptors with preference for extrasynaptic δ-containing receptors; this property may contribute to its broad antiepileptic effectiveness and explain its lack of effect on absence seizures.