Inhibition of GABAA ligand-gated Cl- channels by zinc in adult rat brain: a regional study.
Zinc (Zn2+) was shown to invariably inhibit muscimol-stimulated 36Cl- uptake by synaptoneurosomes in the cerebral cortex, hippocampus and cerebellum. The Zn2+ sensitivity of the GABAA receptor-gated 36Cl- uptake in the cerebral cortex was comparable to that in the hippocampus, whereas the uptake in the cerebellum was less sensitive to Zn2+. Although diazepam-potentiation of muscimol-stimulated 36Cl- uptake was unaltered by 100 microM Zn2+ in the cerebral cortex and hippocampus, diazepam caused no enhancement in the presence of Zn2+ in the cerebellum. Zn2+ inhibited [3H]diazepam binding significantly at 1 mM in the cerebral cortex and cerebellum, whereas Ni2+ increased the binding in a concentration-dependent manner in both regions. Although lower concentrations of Zn2+ did not affect [3H]Ro 15-4513 binding to diazepam-sensitive sites, higher concentrations of ZN2+ increased the binding in both regions. Unlike the diazepam-sensitive sites, the diazepam-insensitive [3H]Ro 15-4513 binding was not affected by Zn2+ or Ni2+ at any of the tested concentrations. These results suggest that the GABAA ligand-gated Cl- flux and its diazepam-potentiation are heterogeneously modulated in various brain regions. It is also suggested that cerebellar diazepam-insensitive [3H]Ro 15-4513 binding sites are insensitive to Zn2+ and Ni2+.
Ito
Y
Y
Department of Pharmacology, College of Pharmacy, Nihon University, Funabashi, Japan. yoshiit@ask.or.jp
Segawa
K
K
Kobayashi
M
M
Fukuda
H
H
D000818:Animals; D001386:Azides / Q000378:metabolism; D001569:Benzodiazepines / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology*; D002712:Chlorides / Q000378:metabolism*; D003975:Diazepam / Q000378:metabolism / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D009928:Organ Specificity; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D014316:Tritium; D015032:Zinc / Q000494:pharmacology*
D001386:Azides; D018118:Chloride Channels; D002712:Chlorides; D011963:Receptors, GABA-A; D014316:Tritium; D001569:Benzodiazepines; D009118:Muscimol; C042957:Ro 15-4513; D015032:Zinc; D003975:Diazepam