In. Sharonova et al., Interaction between copper and zinc at GABA(A) receptors in acutely isolated cerebellar Purkinje cells of the rat, BR J PHARM, 130(4), 2000, pp. 851-856
1 Nanomolar concentrations of Cu2+ induce a slowly reversible block of GABA
(A) receptor-mediated currents which can be removed by chelating substances
.
2 The possible interaction of Cu2+ with the Zn2+ binding site on the GABA(A
) receptor complex was studied in acutely isolated Purkinje cells using who
le-cell recording and a fast drug application system.
3 When Zn2+ was applied together with 2 mu M GABA, the Zn2+-induced block o
f GABA-mediated currents was not additive to the Cu2+-induced block. In the
presence of 0.1 mu M Cu2+ in the bath solution the degree of inhibition of
GABA-mediated responses by Zn2+ was strongly attenuated.
4 Preapplication of 100 mu M Zn2+ during 10 s, terminated 1 s before exposu
re to 2 mu M GABA did not affect the GABA current in Cu2+-free solution, bu
t relieved its block by 0.1 mu M Cu2+. This effect of Zn2+ was concentratio
n-dependent with an EC50 of 72 mu M.
5 When the Cu2+-induced block was removed by histidine, preapplication of Z
n2+ did not increase the GABA current, indicating that the relief of Cu2+ b
lock by Zn2+ is the result of its ability to actively remove Cu2+ from the
GABA receptor complex.
6 It is proposed that the inhibitory effects of Zn2+ and Cu2+ on GABA-induc
ed currents result from an action of these metal ions at distinct, but conf
ormationally linked sites on the GABA(A) receptor protein. Under physiologi
cal conditions Zn2+ would liberate Cu2+ from the GABA(A) receptor, thus fac
ilitating Cu2+ turnover and its binding by other endogenous chelating molec
ules.