The antipsychotic drug loxapine is an opener of the sodium-activated potassium channel slack (Slo2.2)

J Pharmacol Exp Ther. 2012 Mar;340(3):706-15. doi: 10.1124/jpet.111.184622. Epub 2011 Dec 13.

Abstract

Sodium-activated potassium (K(Na)) channels have been suggested to set the resting potential, to modulate slow after-hyperpolarizations, and to control bursting behavior or spike frequency adaptation (Trends Neurosci 28:422-428, 2005). One of the genes that encodes K(Na) channels is called Slack (Kcnt1, Slo2.2). Studies found that Slack channels were highly expressed in nociceptive dorsal root ganglion neurons and modulated their firing frequency (J Neurosci 30:14165-14172, 2010). Therefore, Slack channel openers are of significant interest as putative analgesic drugs. We screened the library of pharmacologically active compounds with recombinant human Slack channels expressed in Chinese hamster ovary cells, by using rubidium efflux measurements with atomic absorption spectrometry. Riluzole at 500 μM was used as a reference agonist. The antipsychotic drug loxapine and the anthelmintic drug niclosamide were both found to activate Slack channels, which was confirmed by using manual patch-clamp analyses (EC(50) = 4.4 μM and EC(50) = 2.9 μM, respectively). Psychotropic drugs structurally related to loxapine were also evaluated in patch-clamp experiments, but none was found to be as active as loxapine. Loxapine properties were confirmed at the single-channel level with recombinant rat Slack channels. In dorsal root ganglion neurons, loxapine was found to behave as an opener of native K(Na) channels and to increase the rheobase of action potential. This study identifies new K(Na) channel pharmacological tools, which will be useful for further Slack channel investigations.

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Antipsychotic Agents / pharmacology*
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / physiology
  • Loxapine / blood
  • Loxapine / pharmacology*
  • Nerve Tissue Proteins / metabolism*
  • Patch-Clamp Techniques
  • Potassium Channels / metabolism*
  • Potassium Channels, Sodium-Activated
  • Rats
  • Rats, Sprague-Dawley
  • Riluzole / pharmacology
  • Rubidium / metabolism

Substances

  • Antipsychotic Agents
  • Nerve Tissue Proteins
  • Potassium Channels
  • Potassium Channels, Sodium-Activated
  • kcnt1 protein, rat
  • Riluzole
  • Loxapine
  • Rubidium