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.
Davies
M F
MF
Molecular Research Institute, Palo Alto, California 94304.
Maguire
P A
PA
Loew
G H
GH
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D018118:Chloride Channels / Q000187:drug effects* / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism*; D002713:Chlorine; D004357:Drug Synergism; D005442:Flumazenil / Q000378:metabolism; D005445:Flunitrazepam / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D007700:Kinetics; D011868:Radioisotopes; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013268:Stimulation, Chemical; D014316:Tritium; D015032:Zinc / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D018118:Chloride Channels; D002712:Chlorides; D058787:GABA-A Receptor Antagonists; D011868:Radioisotopes; D011963:Receptors, GABA-A; D014316:Tritium; D001569:Benzodiazepines; D005442:Flumazenil; D002713:Chlorine; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; D015032:Zinc