The anticonvulsant retigabine suppresses neuronal KV2-mediated currents.

Jeroen I Stas,Dirk J Snyders,Elke Bocksteins,Nicole Schmitt,Camilla S Jensen

doi:10.1038/srep35080

Jeroen I Stas, Dirk J Snyders + Show 3 more

Open Access

https://doi.org/10.1038/srep35080

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Abstract

Enhancement of neuronal M-currents, generated through KV7.2-KV7.5 channels, has gained much interest for its potential in developing treatments for hyperexcitability-related disorders such as epilepsy. Retigabine, a KV7 channel opener, has proven to be an effective anticonvulsant and has recently also gained attention due to its neuroprotective properties. In the present study, we found that the auxiliary KCNE2 subunit reduced the KV7.2-KV7.3 retigabine sensitivity approximately 5-fold. In addition, using both mammalian expression systems and cultured hippocampal neurons we determined that low μM retigabine concentrations had ‘off-target’ effects on KV2.1 channels which have recently been implicated in apoptosis. Clinical retigabine concentrations (0.3–3 μM) inhibited KV2.1 channel function upon prolonged exposure. The suppression of the KV2.1 conductance was only partially reversible. Our results identified KV2.1 as a new molecular target for retigabine, thus giving a potential explanation for retigabine’s neuroprotective properties.

Highlights

Retigabine (RTG) is a novel, ‘first-in-class’ anticonvulsant drug approved for use in partial-onset seizures[6,7]
Of the five known KCNE proteins, KCNE2 potentially interacts with the main determinants of the M-current - heteromeric KV7.2-KV7.3 channels - based on overlapping expression patterns and gating effects[31,32]
KCNE2 reduced the shift in the voltage-dependence of activation (ΔV) at every concentration (Fig. 1e), resulting in a right-shifted concentration-effect curve with an EC50 of 10.0 ± 2.2 μM and a Hill coefficient of 1.0 ± 0.1 (n = 9; Fig. 1f)

Summary

Introduction

Retigabine (RTG) is a novel, ‘first-in-class’ anticonvulsant drug approved for use in partial-onset seizures[6,7]. It was found that the binding of retigabine is dependent on the hydrogen-bonding capability of the indole nitrogen atom in the Trp residue and the amide carbonyl oxygen atom of retigabine[19] This general mechanism for suppression of neuronal excitability makes retigabine and other KV7 activators interesting compounds for several other hyperexcitability-related disorders such as migraine, chronic pain, tinnitus, and even Huntington’s disease[20,21,22,23]. We found that the addition of the auxiliary subunit KCNE2 decreased the retigabine sensitivity of heterotetrameric KV7.2-KV7.3, but not of KV2.1, channels These findings identify KV2.1 as an important molecular target for the action of retigabine and, due to KV2.1’s key role in apoptosis, could help explain the previously reported neuroprotective properties[24,25,26]

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