Zinc selectively inhibits flux through benzodiazepine-insensitive gamma-aminobutyric acid chloride channels in cortical and cerebellar microsacs.

The effects of Zn2+ on the activity of gamma-aminobutyric acid (GABA)A receptor-Cl- ionophore complexes found in adult rat cortex and cerebellum were tested by measuring 36Cl- influx into microsacs. In both preparations, the concentration-response curves were biphasic, with 25% of the cerebellar and 20% of the cortical Cl- flux being blocked by less than 10 microM Zn2+ and 45% of the cerebellar and 50% of the cortical flux being blocked by concentrations of Zn2+ exceeding 10 microM. Zn2+ (100 microM) did not affect basal Cl- flux but inhibited that stimulated by 100 microM GABA in a noncompetitive manner. The ability of 1 microM flunitrazepam to enhance Cl- flux was unaffected by 100 microM Zn2+. These results demonstrate that, in adult rat cerebellum and cortex, there are three populations of GABAA receptors, two that are sensitive to Zn2+ and insensitive to benzodiazepines (BDZ) and the remainder that are the reverse, i.e., insensitive to Zn2+ but fully sensitive to BDZ enhancement. This result is consistent with the idea that Zn2+ blocks only those GABAA receptor-Cl- ionophore complexes that lack a gamma subunit, which is required for modulation by BDZ. The results obtained in this study also show that the proportion of Zn(2+)-sensitive GABA receptors is substantial, suggesting that they play an important role in the functioning of the adult central nervous system.