Uniqueness and redundancy in GABA production

Abstract

GABA is present in organisms belonging to at least four of the five kingdoms. It acts as a neurotransmitter, a paracrine signaling molecule, a metabolic intermediate, or a trophic factor. In mammals, GABA synthesis depends on two forms of the enzyme glutamic acid decarboxylase--GAD65 and GAD67--that may serve distinctive functions within GABA-producing cells. The two GADs derive from two genes, which are differentially regulated, though nearly every GABA-producing cell contains both forms of GAD. GAD67 predominates early in development and after neuronal injury, consistent with a possible role in producing GABA for trophic use. In the embryo, GAD67 transcripts also undergo alternative splicing, which gives rise to truncated forms. In the mature neuron, GAD67 is present in both terminals and the cell body, where it may subserve a nonsynaptic, intracellular GABA pool. In contrast, GAD65 is usually expressed later in development and is primarily localized to nerve terminals. GAD65 enzymatic activity is more subject to regulation by cofactor binding and neuronal activity, consistent with its involvement in the production of synaptic GABA. Thus, while both GAD67 and GAD65 mediate the synthesis of GABA, their unique distributions and expression patterns suggest divergent functional roles.