Review
Two isoforms of glutamate decarboxylase: why?

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Abstract

Adults express two isoforms of glutamate decarboxylase (GAD), GAD67 and GAD65, which are encoded by different independently regulated genes, a situation that differs from that of other neurotransmitters. In this article, J-J. Soghomonian and David Martin review current knowledge on the differences between these two isoforms. Both isoforms are present in most GABA-containing neurones in the CNS, but GAD65 appears to be targeted to membranes and nerve endings, whereas GAD67 is more widely distributed in cells. Both forms can synthesize transmitter GABA, but GAD67 might preferentially synthesize cytoplasmic GABA and GAD65 might preferentially synthesize GABA for vesicular release. Several lines of evidence suggest that the two forms have different roles in the coding of information by GABA-containing neurones.

Section snippets

Biochemical, molecular and subcellular features of the two cloned GADs

GAD67 and GAD65, which are so named because of their approximate molecular weights of 65 400 Da and 66 600 Da, respectively (Ref. [4]), are each composed of two domains, as determined by sequence analysis: a highly divergent N-terminal domain (with 23% identity between the two human GADs) that is involved in subcellular targeting, membrane association and heteromeric interactions11, 12, 13, 14, 15, 16, and a much larger, more conserved (73% identity) C-terminal domain that contains the catalytic

Is GAD67 exclusively involved in the GABA shunt?

In addition to its role in neurotransmission, GABA can feed into the tricarboxylic acid (TCA) cycle. Based on the large amounts of GABA in neuronal cell bodies and the different intraneuronal distributions of GAD65 and GAD67, it has been suggested that GAD67 might be involved in the synthesis of GABA for general metabolic activity, whereas GAD65 is involved in synaptic transmission[21]. On a whole tissue basis, the flux of GABA through the TCA cycle is only a small fraction of the total flux

Are the two GAD isoforms associated with different modes of GABA release?

As shown in neuronal cell cultures or brain slices, GABA can be released through a Ca2+-dependent or -independent mechanism32, 33, 34. In cultured cells from the cerebral cortex, Belhage et al.[34]have shown that preloaded [3H]GABA is released by two mechanisms as a result of high K+ concentrations. The initial and rapid phase of release is sensitive to the colchicine-like drug nocodazole that arrests the transport of vesicles, whereas the second phase is not sensitive to nocodazole, but is

GAD isoforms and the electrophysiology of GABA-containing neurones

Altering the inputs to GABA-containing neurones often modifies the expression of the two GAD isoforms. For example, GAD67 mRNA levels are altered in Purkinje cells after lesions of the inferior olive-climbing fibre system[45], in the cerebral cortex after monocular visual deprivation[46], in the pallidum after suction-induced cortical and striatal damage[47]and in the striatum after electrolytic lesions of inputs from the parafascicular nucleus[41]. In the cerebellum, GAD67 mRNA levels increase

GAD isoforms and the pharmacology of motor control by the basal ganglia

Interactions between dopamine and GABA play an important role in the modulation of locomotor behaviour by the basal ganglia. In Parkinsonian monkeys, removing the dopamine afferents to the basal ganglia with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) increases GAD67 and GAD65 mRNA levels in striatopallidal neurones and in neurones of the internal (the entopeduncular nucleus in rodents) segment of the pallidum48, 49, 56. These increases are consistent with an involvement

GAD isoforms in the pharmacology of sexual behaviour

GABA-containing neurones play an important role in the regulation of lordosis. Stimulation of GABA receptors in the preoptic area inhibits lordosis and activation in the mediobasal hypothalamus or midbrain central grey facilitates lordosis[67]. These behavioural effects might involve a control of secretion of the gonadotropin-releasing hormone by GABA-containing neurones, which would themselves be under the control of gonadal steroids such as oestrogen. The two GAD isoforms might play different

Concluding remarks

We have reviewed experimental evidence for the existence of two isoforms of GAD, GAD65 and GAD67, which are distributed widely in GABA-containing neurones of the CNS. Immunohistochemical and in situ hybridization data indicate that the majority of GABA-containing neurones in the brain coexpress the genes encoding the two GAD isoforms. However, the level of expression of each GAD isoform gene is very heterogeneous at both the regional and cellular level. Also reviewed is the evidence that the

Acknowledgements

J-J. S. was funded by grants from the NSERCC, MRC, Parkinson Foundation of Canada and the Fonds de Recherche en Santé du Québec (FRSQ) and D. L. M. was funded by grant MH35664 from the USPHS.

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