High-affinity copper block of GABA(A) receptor-mediated currents in acutely isolated cerebellar Purkinje cells of the rat

Eur J Neurosci. 1998 Feb;10(2):522-8. doi: 10.1046/j.1460-9568.1998.00057.x.


The actions of Cu2+ ions on GABAA receptor-mediated currents in acutely isolated Purkinje cells from rat cerebellum were studied using the whole-cell patch-clamp technique and a rapid perfusion system. Bath application of Cu2+ reduced currents induced by 2 microM gamma-aminobutyric acid (GABA) in a concentration-dependent manner with an IC50 of 35 nM. The Cu2+-induced block of GABA responses was not voltage-dependent. Increasing the GABA concentration (from 2 to 50 microM) decreased the blocking effect of Cu2+. Dose-response analysis for activation of GABAA receptors revealed a twofold decrease in apparent affinity for GABA in the presence of 0.1 microM Cu2+. Recovery from the block required several minutes after removal of Cu2+ from the medium. The block was removed by histidine, which preferentially forms complexes with Cu2+, or by other chelating substances. Application of 10 microM histidine immediately before application of 2 microM GABA completely relieved the block of GABA responses produced by 0.1 microM Cu2+. The effect of histidine was concentration-dependent with an EC50 of 0.75 microM. The results demonstrate that Cu2+ is a potent inhibitor of GABA-evoked responses in rat Purkinje cells. Copper may be an endogenous synaptic modulating factor. Cu2+ toxicity, notably in Wilson's disease, could result to some extent from chronic GABAA receptor blockade.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chelating Agents / pharmacology
  • Copper / pharmacology*
  • Electric Stimulation
  • Electrophysiology
  • GABA-A Receptor Antagonists*
  • In Vitro Techniques
  • Ion Channels / drug effects
  • Ion Channels / metabolism*
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Patch-Clamp Techniques
  • Purkinje Cells / drug effects
  • Purkinje Cells / metabolism*
  • Rats


  • Chelating Agents
  • GABA-A Receptor Antagonists
  • Ion Channels
  • Copper