Negative modulation of the gamma-aminobutyric acid response by extracellular zinc

We have studied the effects of divalent cations on the gamma-aminobutyric acid (GABA) response of voltage-clamped spinal cord neurons, using the whole-cell recording configuration. Zn, Cd, Ni, and Mn (but not Ba, Ca, or Mg) inhibit GABA-induced whole-cell currents when applied extracellularly. Although Zn is an effective inhibitor when applied extracellularly, it is ineffective when applied intracellularly. Inhibition by these cations is mediated by a common saturable recognition site that is distinct from the recognition sites for GABA, benzodiazepines, barbiturates, picrotoxin, or steroids. The maximal inhibition, or efficacy of inhibition, of GABA-induced currents is greater for Zn than for Cd, Ni, or Mn. The order of potency is Cd greater than Zn much greater than Ni much greater than Mn. Inhibition by Zn is partially surmountable by GABA, consistent with a decrease in both the maximum response and the affinity for GABA. The dose-response curve for inhibition of the GABA response by Zn is shifted to the right at a high GABA concentration but is unaffected by the presence of chlordiazepoxide, pentobarbital, or 5 beta-pregnan-3 alpha-ol-20-one. The results are consistent with a model in which a Zn-sensitive modulatory site exerts negative allosteric control over GABA receptor function.