Alan D. Wickenden

Epilepsy and neuropathic pain are disorders characterised by excessive neuronal activity. These disorders are currently managed by drugs that are capable of dampening neuronal excitability, including voltage-gated sodium channel blockers, voltage-operated calcium channel modulators and modulators of inhibitory GABAergic neurotransmission. However, these drugs are rarely 100% efficacious and their use is often associated with limiting side effects. Thus, there is a clear medical need for novel agents to treat these diseases. One potential mechanism that has not yet been exploited is potassium (K⁺) channel opening. A significant (and growing) body of genetic, molecular, physiological and pharmacological evidence now exists to indicate that KCNQ-based currents represent particularly interesting targets for the treatment of diseases such as epilepsy and neuropathic pain. Evidence supporting these K⁺ channels as novel drug targets will be reviewed in the following article. Worldwide patent activity relating to KCNQ channels and KCNQ-modulating drugs and their uses will also be summarised.

Heteromeric KCNQ5/Q3 channels were stably expressed in Chinese Hamster ovary cells and characterized using the whole cell voltage‐clamp technique. KCNQ5/Q3 channels were activated by the novel anticonvulsant, retigabine (EC₅₀ 1.4 μM) by a mechanism that involved drug‐induced, leftward shifts in the voltage‐dependence of channel activation (−31.8 mV by 30 μM retigabine). KCNQ5/Q3 channels were inhibited by linopirdine (IC₅₀ 7.7 μM) and barium (IC₅₀ 0.46 mM), at concentrations similar to those required to inhibit native M‐currents. These findings identify KCNQ5/Q3 channels as a molecular target for retigabine and raise the possibility that activation of KCNQ5/Q3 channels may be responsible for some of the anti‐convulsant activity of this agent. Furthermore, the sensitivity of KCNQ5/Q3 channels to linopirdine supports the possibility that potassium channels comprised of KCNQ5 and KCNQ3 may make a contribution to native M‐currents.British Journal of Pharmacology (2001) 132, 381–384; doi:10.1038/sj.bjp.0703861

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 μM) 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 μM), and 82.7 ± 5.4% (n = 4) by BaCl₂ (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 μM retigabine). Retigabine shifted the voltage dependence of channel activation with an EC₅₀value of 1.6 ± 0.3 μM (slope factor was 1.2 ± 0.1,n = 4 to 5 cells per concentration). Retigabine (0.1 to 10 μM) 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.