Understanding molecular mechanisms subserving control of glutamate and glutamine production and utilization in brain and peripheral organs is of crucial importance because these amino acids serve many vital functions in neurons and glial cells. Glutamate is an excitatory neurotransmitter and at higher concentrations is toxic to the brain. Glutamine functions as: (i) a precursor of glutamate, gamma aminobutyric acid, purines and pyrimidines, (ii) a protein constituent, (iii) respiratory fuel, and (iv) detoxification product of ammonia. Glutamine production and utilization are dynamically coupled to glutamate. Glutamate is compartmentalized, most likely because of the localization of glutamine synthetase and glutaminase in specific cell constituents and cell types. Compartmentation adds an additional level ot complexity to the control of glutamine and glutamate metabolism in the brain. Our research will focus on (i) the transcriptional control of glutamine synthetase and glutaminase, (ii) the post-transcriptional control of these enzymes by intracellular effectors, and (iii) compartmentation of glutamate and its effect on glutamate and glutamine metabolism in brain. The objective of the proposed studies is to increase our knowledge of these mechanisms via detailed and comprehensive investigations into the control of gene expression and intracellular regulation of glutamine synthetase (the enzyme that synthesizes glutamine), and glutaminase (the enzyme that converts glutamine to glutamate), and glutamate decarboxylase. The expression of these enzymes appears to be controlled by a multiplicity of effectors, including substrate and product (glutamine inhibits while glutamate stimulates glutamine synthetase, whereas glutamate inhibits and glutamine stimulates glutaminase), glucocorticoids, and cyclic AMP. These multiple modes of control of glutamine synthetase and degradation afford great flexibility in regulating the production and utilization of these vital amino acids. An important objective of our studies is to understand the integration of these various influences on the expression of glutamine synthetase and glutaminase. Alterations of any of these regulatory mechanisms could lead to neurological dysfunction. Abnormalities of glutamate function have been implicated in neurodegenerative disorders such as olivopontocerebellar degeneration, epilepsy, and neurotoxicity during ischemia. Therefore, the proposed studies will emphasize the close relationship of glutamine and glutamate and their relation to abnormal brain function. A major advantage of the proposed studies Is the combination of cellular and molecular biological approaches to this important problem.
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