UNIQUENESS AND REDUNDANCY IN GABA PRODUCTION

GABA is present in organisms belonging to at least four of the five ki ngdoms. It acts as a neurotransmitter, a paracrine signaling molecule, a metabolic intermediate, or a trophic factor. In mammals, GABA synth esis depends on two forms of the enzyme glutamic acid decarboxylase-GA D(65), and GAD(67)-that may serve distinctive functions within GABA-pr oducing cells. The two GADs derive from two genes, which are different ially regulated, though nearly every GABA-producing cell contains both forms of GAD. GAD(67) predominates early in development and after neu ronal injury, consistent with a possible role in producing GABA for tr ophic use. In the embryo, GAD(67) transcripts also undergo alternative splicing, which gives rise to truncated forms. In the mature neuron, GAD(67) is present in both terminals and the cell body, where it may s ubserve a nonsynaptic, intracellular GABA pool. In contrast, GAD(65) i s usually expressed later in development and is primarily localized to nerve terminals. GAD(65) enzymatic activity is more subject to regula tion by cofactor binding and neuronal activity, consistent with its in volvement in the production of synaptic GABA. Thus, while both GAD(67) and GAD(65) mediate the synthesis of GABA, their unique distributions and expression patterns suggest divergent functional roles.