Glutamate, aspartate and the acidic amino acid receptors constitute significant mechanisms of excitatory neurotransmission with broad relevance to normal nervous system function and to such diverse conditions as epilepsy, schizophrenic psychoses and neurodegenerative disorders including stroke/anoxia/hypoglycemia induced cell death. A dipeptide derived from these amino acids, N-acetylaspartylglutamate, (NAAG) is present specifically in the nervous system at very high concentrations. The synaptic release of NAAG upon depolarization supports speculation that it participates in cellular communication. The long term objective of this research project is to define the anatomical, metabolic and functional relationships between NAAG and the excitatory amino acids, glutamate and aspartate.
The specific aims are to test three hypotheses: 1. elevated levels of glutamate, aspartate and NAAG are restricted to different populations of neurons; 2. upon synaptic release, enzymes act on NAAG to release significant amounts of glutamate, acetylaspartate and aspartate; 3. NAAG acts through subclasses of acidic amino acid receptors to activate second messenger responses, as has been shown for glutamate. The role of NAAG as a source of glutamate or as an acidic receptor agonist is a relatively unexplored topic which will be addressed with analysis of: I. the codistribution of glutamatergic, aspartergic and NAAGergic neurons via immunohistochemistry and radioimmunoassay. II. the kinetics of NAAG metabolism with RIA after synaptic release and the metabolism of exogenous 3H-NAAG by several neuronal systems; III. the influence of NAAG on phosphoinositol metabolism, release of arachidonic acid, and accumulation of cGMP in nervous system preparations in which glutamate has been shown to affect these second messenger responses via discrete subclasses of acidic receptors.
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