Differential effects of zinc on native GABA(A) receptor function in rat hippocampus and cerebellum.
Hippocampal noradrenergic and cerebellar glutamatergic granule cell axon terminals possess GABA(A) receptors mediating enhancement of noradrenaline and glutamate release, respectively. The hippocampal receptor is benzodiazepine-sensitive, whereas the cerebellar one is not affected by benzodiazepine agonists, indicating the presence of an alpha6 subunit. We tested here the effects of Zn2+ on these two native GABA(A) receptor subtypes using superfused rat hippocampal and cerebellar synaptosomes. In the cerebellum, zinc ions strongly inhibited (IC50 approximately 1 microM) the potentiation of the K(+)-evoked [3H]D-aspartate release induced by GABA. In contrast, the GABA-evoked release of [3H]noradrenaline from hippocampal synaptosomes was much less sensitive to Zn2+ (IC50 > 30 microM). The effects of Zn2+ were then studied in two rat lines selected for high (ANT) and low (AT) alcohol sensitivity because granule cell GABA(A) receptors in ANT, but not AT, rats respond to benzodiazepine agonists due to a critical mutation in the alpha6 subunit. GABA increased the K(+)-evoked release of [3H]DCNS REGIONS-aspartate from cerebellar synaptosomes of AT and ANT rats, an effect prevented by the GABAA selective antagonist bicuculline. In AT rat cerebellum, the effect of GABA was strongly inhibited by Zn2+ (IC50 < or = 1 microM), whereas in ANT rats, the divalent cation was about 100-fold less potent. Thus, native benzodiazepine-sensitive GABAA receptors appear largely insensitive to functional inhibition by Zn2+ and vice versa. Changes in sensitivity to Zn2+ inhibition consequent to mutations in cerebellar granule cell GABA(A) receptor subunits may lead to changes in glutamate release from parallel fibers onto Purkinje cells and may play important roles in cerebellar dysfunctions.
Dipartimento di Medicina Sperimentale, Sezione di Farmacologia e Tossicologia, Genova, Italy.
G
G
Schmid
R
R
Chittolini
L
L
Raiteri
G
G
Bonanno
D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects / Q000502:physiology*; D004357:Drug Synergism; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology*; D013574:Synaptosomes / Q000187:drug effects / Q000502:physiology; D014316:Tritium; D015032:Zinc / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D011963:Receptors, GABA-A; D014316:Tritium; D001224:Aspartic Acid; D005680:gamma-Aminobutyric Acid; D015032:Zinc; D011188:Potassium; D009638:Norepinephrine