Zinc is a mixed antagonist of homomeric ρ1 γ-aminobutyric acid-activated channels

The transition metal Zn²⁺ is differentially distributed in the central nervous system, where it is proposed to be a neuromodulator. One of the documented effects of Zn²⁺ is the antagonism of γ-aminobutyric acid (GABA)-mediated synaptic inhibition. This antagonism is presumed to result from a direct interaction of Zn²⁺ with the GABA receptor/ionophore complex, although the characteristics of Zn²⁺ sensitivity are dependent on the particular GABA subunit combination. In this study, we examined the effects of Zn²⁺ on homomeric ρ1 GABA-activated channels expressed in Xenopus oocytes. Zn²⁺ was found to be a mixed antagonist of these recombinant ρ1 GABA receptors. The antagonism was predominately competitive at low Zn²⁺ concentrations (≤100 μM), whereas at high Zn²⁺ concentrations (>100 μM) a noncompetitive antagonism was apparent. Evidence is presented showing that the antagonism was not due to an interaction of GABA and Zn²⁺ in solution but, rather, resulted from interactions of these two ligands with the GABA- activated channel. A mechanism is proposed for Zn²⁺mediated antagonism in which GABA and Zn²⁺ bind to distinct sites on the GABA complex. The apparent mixed antagonism may arise from different K(i) values for the binding of Zn²⁺ to non-agonist-bound or agonist-bound receptors. However, two distinct Zn²⁺ binding sites, one competitive and one noncompetitive, could also give rise to the dual antagonism.