Differential blockade of neuronal voltage-gated Na+ and K+ channels by antidepressant drugs

Graham M. Nicholson, Tim Blanche, Kylie Mansfield, Yvonne Tran

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

The effects of a range of antidepressants were investigated on neuronal voltage-gated Na+ and K+ channels. With the exception of phenelzine, all antidepressants inhibited batrachotoxin-stimulated 22Na+ uptake, most likely via negative allosteric inhibition of batrachotoxin binding to neurotoxin receptor site-2 on the Na+ channel. Imipramine also produced a differential action on macroscopic Na+ and K+ channel currents in acutely dissociated rat dorsal root ganglion neurons. Imipramine produced a use-dependent block of Na+ channels. In addition, there was a hyperpolarizing shift in the voltage-dependence of steady-state Na+ channel inactivation and slowed repriming kinetics consistent with imipramine having a higher affinity for the inactivated state of the Na+ channel. At higher concentrations, imipramine also blocked delayed-rectifier and transient outward K+ currents in the absence of alterations to the voltage-dependence of activation or the kinetics of inactivation. These actions on voltage-gated ion channels may underlie the therapeutic and toxic effects of these drugs.

Original languageEnglish
Pages (from-to)35-48
Number of pages14
JournalEuropean Journal of Pharmacology
Volume452
Issue number1
DOIs
Publication statusPublished - 27 Sep 2002
Externally publishedYes

Keywords

  • Na flux
  • Antidepressant
  • Imipramine
  • K channel
  • Na channel
  • Patch clamping

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