The amino acids, glutamate and aspartate, are the predominant excitatory neurotransmietters in the central nervous system. The levels of both of these amino acids approach 10 mmol/kg in brain tissue. Under normal conditions, the extracellular concentrations are maintained below .001-.010 M. In many acute neurologic diseases, including ischemia, head trauma, and epilepsy, the extracellular concentrations of these amino acids increase dramatically and the subsequent excessive activation of receptors contributes to the pathophysiology. Many investigators have focused on the postsynaptic mechanisms involved in this """"""""excitotoxicity"""""""". The transport process that regulates the extracellular concentration of these amino acids is not well characterized. It is known that the extracellular concentrations of glutamate and aspartate are maintained at low levels by a sodium-dependent high affinity transport process. Data support the presence of at least two subtypes of this transport process with heterogeneous distributions. Studies will be carried out to test the hypotheses that there are subtypes of transport, that these subtypes have different distributions and that these subtypes can be independently regulated. Biochemical, pharmacological, and morphological techniques will be used to characterize these subtypes of transport and their regulation. The long-term goal of these studies is to define the functional relevance of these subtypes of transport systems. The objective of these studies are: 1) To compare the kinetic properties, the ion-dependence, the inhibition by excitatory amino acid analogs, and the sensitivity to sulfhydryl modifying reagents of the transport subtypes. 2) To determine the regional and cellular distribution of these subtypes of transport. 3) To characterize the mechanism(s) that regulate transport activity, including regulation by second messenger systems, including the phosphoinositide and cAMP cascades and regulation by its substrates. Subtypes of transport systems may provide a mechanism for specificity and regulation of synaptic transmission analogous to the specificity of postsynaptic signaling provided by receptor subtypes. Consistent with the diverse functions of these amino acids, metabolic and neurotransmitter pools of the excitatory amino acids are regulated independently in brain tissue. Heterogeneity of the excitatory amino acid transport systems may provide a mechanism for compartmentalization and regulation of excitatory amino acid metabolish. Characterization of the excitatory amino acid transport system(s) will help to define the role of this transport system in synaptic signaling, metabolic compartmentalization, and excitotoxic neuronal degeneration.
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