State-dependent regulation of the Kv7.2 channel voltage sensor by QO-58.

Background and purpose: K_V7(KCNQ) potassium channels are key modulators of neuronal excitability, and promising targets for development of drugs for epilepsy and pain. We investigated a candidate K_V7 drug, QO-58, which has been previously described but has an unclear mechanism of action.

Experimental approach: Targeted mutations or chimeric rearrangements of K_V7 channels were used to investigate potential sites of drug binding. K_V7 channels were expressed in Xenopus oocytes or HEK cells for electrophysiology and pharmacological characterisation.

Key results: QO-58 shares characteristic features of other voltage sensor domain (VSD)-targeted potentiators. These include subtype specificity for K_V7.2 over K_V7.3, prominent state-dependent actions, and marked deceleration of closure of K_V7.2. VSD mutations influence the actions of QO-58 and another VSD-targeted drug, ICA-069673. Interestingly, K_V7.2[F168L] mutation, previously shown to abolish ICA-069673 sensitivity, does not weaken QO-58 actions. However, K_V7.2[F168W] reduces QO-58 effects, while preserving sensitivity to ICA-069673. This finding indicates subtle differences in the interaction of these drugs with the VSD binding site.

Conclusions and implications: Key contacts underlying sensitivity to VSD-targeted potentiators may vary significantly depending on the chemical and steric features of the drug. We anticipate that further investigation of VSD-targeted drugs will continue to clarify the complex pharmacophore of the VSD binding pocket in K_V7 channels.