Clofilium inhibits Slick and Slack potassium channels

Abstract

Slick and Slack high-conductance potassium channels have been recently discovered, and are found in the central nervous system and in the heart. Both channels are activated by Na⁺ and Cl⁻, and Slick channels are also inhibited by adenosine triphospate (ATP). An important role of setting the resting membrane potential and controlling the basal excitability of neurons has been suggested for these channels. In addition, no specific blockers for these channels are known up to the present. With the purpose of studying the pharmacological characteristics of Slick and Slack channels, the effects of exposure to the antiarrhythmic compound clofilium were evaluated. Clofilium was able to modulate the activity of Slick and Slack channels effectively, with a stronger effect on Slack than Slick channels. In order to evaluate the pharmacological behavior of Slick and Slack channels further, 38 commonly used potassium channel blockers were tested. Screening of these compounds did not reveal any modulators of Slick and Slack channels, except for clofilium. The present study provides a first approach towards elucidating the pharmacological characteristics of Slick and Slack channels and could be the basis for future studies aimed at developing potent and specific blockers and activators for these channels.

Keywords:

• Slo2.1
• Slo2.2
• clofilium
• potassium channel blockers

Acknowledgments

Ms Z Rasmussen is thanked for her expert technical assistance. This work was supported by grants from The Danish Medical Research Council, The Carlsberg Foundation, The Novo Nordic Foundation, The Lundbeck Foundation (Lucens), and The Fougner-Hartmann Foundation.

Disclosure

The authors declare no conflicts of interest, financial or otherwise, in this work.