Br J Pharmacol 2025 Sep 12; doi: 10.1111/bph.70186.

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

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BACKGROUND AND PURPOSE: KV7(KCNQ) potassium channels are key modulators of neuronal excitability, and promising targets for development of drugs for epilepsy and pain. We investigated a candidate KV7 drug, QO-58, which has been previously described but has an unclear mechanism of action. EXPERIMENTAL APPROACH: Targeted mutations or chimeric rearrangements of KV7 channels were used to investigate potential sites of drug binding. KV7 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 KV7.2 over KV7.3, prominent state-dependent actions, and marked deceleration of closure of KV7.2. VSD mutations influence the actions of QO-58 and another VSD-targeted drug, ICA-069673. Interestingly, KV7.2[F168L] mutation, previously shown to abolish ICA-069673 sensitivity, does not weaken QO-58 actions. However, KV7.2[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 KV7 channels.

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