Abstract
Background/Aims: The neuronal KV7 family members (K V7.2-5) are important regulators of neuronal excitability. K V7 channel openers are therefore attractive drug candidates for the treatment of several hyperexcitability disorders. While most described K V7 channel openers discriminate poorly between KV7.2-5, Icagen's N-(6-chloropyridin-3-yl)-3,4-difluorobenzamide (ICA-27243) is more potent at KV7.2/3 than at KV7.4 and KV7.3/5 and offers some progress towards subtype selectivity. We have investigated its mode of action on KV7.2 and KV7.4, 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 KV7.2, ICA-27243 induced a voltage-independent current on this subtype, which was not observed on K V7.4. Additionally, the combined treatment of KV7.2 and KV7.4 with retigabine and ICA-27243 revealed that the effect of ICA-27243 on KV7.2 dominates that of retigabine, while the compounds act additively and synergistically on KV7.4. Conclusions: These results offer further detailed insight into pharmacological activation of K V7 channels and offer evidence of differential functional and subtype-specific effects by activation of different binding sites in the K V7 channels.
| Original language | English |
|---|---|
| Journal | Pharmacology |
| Volume | 86 |
| Issue number | 3 |
| Pages (from-to) | 174-81 |
| Number of pages | 8 |
| ISSN | 0031-7012 |
| DOIs | |
| Publication status | Published - Sept 2010 |