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 cerebe llum were tested by measuring Cl-36- influx into microsacs. in both pr eparations, the concentration-response curves were biphasic, with 25% of the cerebellar and 20% of the cortical Cl-flux being blocked by les s than 10 mum Zn2+ and 45% of the cerebellar and 50% of the cortical f lux being blocked by concentrations of Zn2+ exceeding 10 mum. Zn2+ (10 0 mum) did not affect basal Cl- flux but inhibited that stimulated by 100 mum GABA in a noncompetitive manner. The ability of 1 mum flunitra zepam to enhance Cl- flux was unaffected by 100 mum Zn2+ . These resul ts demonstrate that, in adult rat cerebellum and cortex, there are thr ee populations of GABA(A) receptors, two that are sensitive to Zn2+ an d insensitive to benzodiazepines (BDZ) and the remainder that are the reverse, i.e., insensitive to Zn2+ but fully sensitive to BDZ enhancem ent. This result is consistent with the idea that Zn2+ blocks only tho se GABA(A) 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 Zn2+-sensitive GABA receptors is substantial, suggesting that they play an important role in the fun ctioning of the adult central nervous system.