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The Level of GAD 67 Protein Is Highly Sensitive to Small Increases in Intraneuronal γ‐Aminobutyric Acid Levels
Author(s) -
Rimvall Karin,
Martin David L.
Publication year - 1994
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1994.62041375.x
Subject(s) - glutamate decarboxylase , chemistry , gamma aminobutyric acid , glutamate receptor , endocrinology , medicine , enzyme , biochemistry , gabaergic , biology , receptor
Increases (>2.5‐fold) in GABA levels in rat brain lead to a large decrease in the level of the 67‐kDa form of glutamate decarboxylase (GAD 67 ) through a mechanism involving either a change in GAD 67 protein stability or a change in GAD 67 mRNA translation. In the present study, brain levels of GABA were manipulated by treating rats with various doses of γ‐vinyl‐γ‐aminobutyric acid (GVG), and the dependence of total GAD activity and levels of GAD 67 and GAD 65 protein on the levels of GABA was analyzed. Initial studies showed that both GABA and GAD 67 protein levels reached new steady‐state levels after two to four daily injections; GABA increased 1.5‐ (30 mg of GVG/kg) and fourfold (150 mg of GVG/kg), and GAD 67 protein content decreased by 30 and 70%. To assess the sensitivity of GAD 67 to GABA, rats were injected with eight different doses of GVG (15‐150 mg/kg) for 5 days. With increasing doses of GVG, we observed a gradual increase in both whole‐tissue and synaptosomal GABA levels and a gradual decrease in GAD 67 protein and GAD activity. The levels of GAD 67 remained constant at all GVG doses. GAD 67 was remarkably sensitive to GABA. The synaptosomal GAD 67 level decreased ∼12% and the whole‐neuron GAD 67 level decreased ∼3% for each 1 % increase in nerve terminal GABA content when it was close to its physiological level. Our results clearly demonstrate that GAD 67 is tightly controlled by intraneuronal GABA, and we suggest that this regulatory mechanism has important implications for the physiological regulation of GABAergic function in the mammalian brain.