Abstract
Background/Aims: The neuronal K<sub>V</sub>7 family members (K<sub>V</sub>7.2–5) are important regulators of neuronal excitability. K<sub>V</sub>7 channel openers are therefore attractive drug candidates for the treatment of several hyperexcitability disorders. While most described K<sub>V</sub>7 channel openers discriminate poorly between K<sub>V</sub>7.2–5, Icagen’s N-(6-chloropyridin- 3-yl)-3,4-difluorobenzamide (ICA-27243) is more potent at K<sub>V</sub>7.2/3 than at K<sub>V</sub>7.4 and K<sub>V</sub>7.3/5 and offers some progress towards subtype selectivity. We have investigated its mode of action on K<sub>V</sub>7.2 and K<sub>V</sub>7.4, compared its effect to that of retigabine and studied the combinatorial effect of retigabine and ICA-27243, as these two compounds recognize different binding sites in the channels. Methods: The effects of ICA-27243 and retigabine were studied using voltage-clamp electrophysiology in Xenopus laevis oocytes and rubidium flux in Chinese hamster ovary cells. Results: We found that in contrast to retigabine’s voltage-dependent action on K<sub>V</sub>7.2, ICA-27243 induced a voltage-independent current on this subtype, which was not observed on K<sub>V</sub>7.4. Additionally, the combined treatment of K<sub>V</sub>7.2 and K<sub>V</sub>7.4 with retigabine and ICA-27243 revealed that the effect of ICA-27243 on K<sub>V</sub>7.2 dominates that of retigabine, while the compounds act additively and synergistically on K<sub>V</sub>7.4. Conclusions: These results offer further detailed insight into pharmacological activation of K<sub>V</sub>7 channels and offer evidence of differential functional and subtype-specific effects by activation of different binding sites in the K<sub>V</sub>7 channels.
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