Interaction between copper and zinc at GABA A receptors in acutely isolated cerebellar Purkinje cells of the rat

Nanomolar concentrations of Cu 2+ induce a slowly reversible block of GABA A receptor‐mediated currents which can be removed by chelating substances. The possible interaction of Cu 2+ with the Zn 2+ binding site on the GABA A receptor complex was studied in acutely isolated Purkinje cells using whole‐cell recording and a fast drug application system. When Zn 2+ was applied together with 2 μ M GABA, the Zn 2+ ‐induced block of GABA‐mediated currents was not additive to the Cu 2+ ‐induced block. In the presence of 0.1 μ M Cu 2+ in the bath solution the degree of inhibition of GABA‐mediated responses by Zn 2+ was strongly attenuated. Preapplication of 100 μ M Zn 2+ during 10 s, terminated 1 s before exposure to 2 μ M GABA did not affect the GABA current in Cu 2+ ‐free solution, but relieved its block by 0.1 μ M Cu 2+ . This effect of Zn 2+ was concentration‐dependent with an EC 50 of 72 μ M . When the Cu 2+ ‐induced block was removed by histidine, preapplication of Zn 2+ did not increase the GABA current, indicating that the relief of Cu 2+ block by Zn 2+ is the result of its ability to actively remove Cu 2+ from the GABA receptor complex. It is proposed that the inhibitory effects of Zn 2+ and Cu 2+ on GABA‐induced currents result from an action of these metal ions at distinct, but conformationally linked sites on the GABA A receptor protein. Under physiological conditions Zn 2+ would liberate Cu 2+ from the GABA A receptor, thus facilitating Cu 2+ turnover and its binding by other endogenous chelating molecules.British Journal of Pharmacology (2000) 130 , 851–856; doi: 10.1038/sj.bjp.0703392