Glutamate is an excitatory neurotransmitter in the mammalian central nervous system and the precursor of the inhibitory neurotransmitter GABA. The enzymes which control glutamate's metabolism 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. We have also found that GA and GDH mRNAs are induced 6-fold and 3-fold, respectively, in the kidneys of acidotic animals. 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 identified two additional GLUD loci in humans which may be pseudogenes. The brain from a patient diagnosed as """"""""GDH-deficient OPCA"""""""" was shown to have normal levels of GDH enzyme and mRNA, casting doubt on the association of GDH deficiency with neurodegenerative disease.
