Glutamate is an excitatory neurotransmitter in the mammalian central nervous system and the precursor of the inhibitory neurotransmitter GABA. The enzymes which control the metabolism of glutamate must have special roles in the brain, different from their roles in other organs. Neuronal glutamate is largely derived from glutamine by a glutaminase (GA) which is similar or identical to that found in kidney, but different from liver glutaminase. Glutamate dehydrogenase (GDH), a key enzyme for ureagenesis and pH homeostasis in liver and kidney, is abundant in brain but without a known role. We have isolated cDNAs for GDH and GA and shown that they are differentially expressed in neurons and astrocytes; we have also shown that a three-fold induction of GA is closely correlated with the development of glutamatergic function in neurons differentiating in culture. In the brains of hyperammonemic animals, GDH gene expression is decreased whereas GA expression is increased. We have also found that GA and GDH mRNAs are induced in the kidneys of acidotic animals. Brain and liver express the same GDH but different GA genes. We have mapped GDH genes (GLUD) to chromosomes 14 in the mouse and 10 in humans, and GA genes (GLS) to chromosomes 1 in mouse, 9 in rat, and 2 in humans. We have also discovered a human restriction fragment length polymorphism (RFLP) for GDH; this provides a tool with which to investigate reports of a connection between low GDH activity and certain inherited neurodegenerative diseases (e.g., olivopontocerebellar atrophy, """"""""OPCA"""""""").
