High-affinity copper block of GABA(A) receptor-mediated currents in acutely isolated cerebellar Purkinje cells of the rat.
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.
Sharonova
I N
IN
Department of Neurophysiology, Heinrich-Heine-Universität, Düsseldorf, Germany.
Vorobjev
V S
VS
Haas
H L
HL
D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000494:pharmacology*; D004558:Electric Stimulation; D004594:Electrophysiology; D058787:GABA-A Receptor Antagonists; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism*; D051381:Rats
D002614:Chelating Agents; D058787:GABA-A Receptor Antagonists; D007473:Ion Channels; D003300:Copper