γ-Aminobutyrate (GABA) is a major inhibitory neurotransmitter in the adult mammalian brain. GABA is also considered to be a multifunctional molecule that has different situational functions in the central nervous system, the peripheral nervous system, and in some nonneuronal tissues. GABA is synthesized primarily from glutamate by glutamate decarboxylase (GAD), but alternative pathways may be important under certain situations. Two types of GAD appear to have significant physiological roles. GABA functions appear to be triggered by binding of GABA to its ionotropic receptors, GABAAand GABAC, which are ligand-gated chloride channels, and its metabotropic receptor, GABAB. The physiological, pharmacological, and molecular characteristics of GABAA receptors are well documented, and diversity in the pharmacologic properties of the receptor subtypes is important clinically. In addition to its role in neural development, GABA appears to be involved in a wide variety of physiological functions in tissues and organs outside the brain.

GABA and GABA receptors in the central nervous system and other organs.

Publisher Summary This chapter discusses the important roles of glutamate and gamma-aminobutyric acid (GABA) in brain metabolism. The chapter shows the amino acids as excitatory and inhibitory transmitters in the CNS. The inactivation of these transmitters is generally brought about by sodium-dependent high-affinity uptake systems rather than enrymatic degradation. The importance of the different cell types in these processes and the characteristics of the different transport systems are discussed. The quantitative importance of the high-affinity uptake of glutamate and GABA into glial cells is investigated in primary cultures of astrocytes that seem to constitute a valid model for such cells in vivo. From these studies, it can be concluded that astrocytes are quantitatively important for uptake of putative transmitter amino acids. Whether this uptake has to do primarily with the transmitter pools of these amino acids, and hence their inactivation, or the uptake is involved in the metabolic processes remains to be finally elucidated. The fact that the processes of astrocytes control a large surface area around synapses seems to favor a function of such cells in the inactivation of these amino acids.On the other hand, it is undoubtedly correct that these amino acids can be taken up into presynaptic nerve endings through high-affinity transport processes. In the case of GABA, it is even possible to distinguish between these transport mechanisms employing inhibitors that have been shown to be selective for the transport carriers.

Transport and metabolism of glutamate and GABA in neurons are glial cells.

Incubation of rat brain 4-aminobutyrate aminotransferase with 4-amino-hex-5-enoic acid, a substrate analog of 4-aminobutyric acid, results in a time-dependent irreversible loss of enzymatic activity. In the presence of 0.1 mM inhibitor the half-life of the inactivation process is approximately 6 min. Low concentrations of L-glutamic acid or 4-aminobutyric acid protect against this inactivation, while 2-oxoglutarate prevents this protection, suggesting that only the pyridoxal form of the enzyme is susceptible to inhibition by 4-amino-hex-5-enoic acid. The irreversible inhibition of mammalian 4-aminobutyrate aminotransferase by 4-amino-hex-5-enoic acid is selective. There is no inhibition of this enzyme from Pseudomonas fluorescens with the inhibitor at mM concentrations. Even at 10 mM there is no irreversible inhibition of mammalian glutamate decarboxylase or of aspartate aminotransferase, while alanine aminotransferase is inhibited over 500 times more slowly than rat brain 4-aminobutyrate transaminase.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1977.tb11410.x

4‐Amino‐hex‐5‐enoic Acid, a Selective Catalytic Inhibitor of 4‐Aminobutyric‐Acid Aminotransferase in Mammalian Brain

Recent advances in metallohistochemistry have substantiated the identification of a distinct class of neurons in the brain, the zinc-containing neurons. These neurons sequester peculiar amounts of zinc in their presynaptic boutons and show both high-affinity uptake and calcium- and impulse-dependent release of the cation. It is thought that the zinc may act to stabilize the storage of certain macromolecules in presynaptic vesicles, but there is also mounting evidence that zinc released from vesicles can produce a broad spectrum of neuromodulatory effects upon target cells. Zinc-containing neurons are found predominantly in limbic and cerebrocortical regions, and a possible role of these neurons in the modification of synaptic strength is considered.

Zinc-containing neurons in hippocampus and related CNS structures.

Tissue and subcellular distribution of mammalian aldehyde-oxidizing capacity

PREVIOUS reports from this laboratory have detailed the fluorimetric measurement of glutamate decarboxylase (GDC) (LOWE, ROBINS and EYERMAN, 1958) and the enzymic fluorimetric measurement of y-aminobutyric acid (GABA) (HIRSCH and ROBINS, 1962) in 3-5 pg lyophilized sections of the layers of cerebellar and cerebral cortex. This report is of the development of a sensitive and specific fluorimetric enzymic assay for y-aminobutyric-cr-oxoglutaric transaminase (GABA-T) activity applicable to 0-2-2-0 pg sections of lyophilized neural tissue, and of the levels obtained in various neural regions in several mammalian species. This method demonstrates small, but appreciable, GABA-T rates in white matter, where it was previously reported as not present. The development of this method is one portion of a larger project to study the biochemistry and physiological significance of the GABA pathway in single cells of the nervous system. EXPERIMENTAL

The enzymic measurement of gamma-aminobutyric-alpha-oxoglutaric transaminase.

A METHOD for measurement of brain succinate semialdehyde dehydrogenase was reported (PITTS and QUICK, 1965) which is sensitive enough to allow assay of 0.01 pg freeze-dried brain samples. This method, based on the fluorescence of NADH, was highly reproducible over a wide range of brain concentrations. In freshly reconstituted freeze-dried whole brain homogenates, succinate semialdehyde dehydrogenase activities for adults of various species were: rat 2000, guinea pig 1400, mouse 1400, and rabbit 750-m-moles per kg dry wt. per hr. Succinate semialdehyde dehydrogenase rates for cerebellar layers, white tracts, and regions of spinal cord of rabbit and monkey were also reported. Brain succinate semialdehyde dehydrogenase has high substrate specificity (PITTS and QUICK, 1965); the nonspecific aldehyde dehydrogenase of brain probably does not oxidize succinate semialdehyde and has a maximal activity with other substrates less than 0.01 that of succinate semialdehyde dehydrogenase (ERVIN and DEITRICH, 1966). A systematic study of succinate semialdehyde dehydrogenase in developing rat brain is the subject of this report. The data include enzymic rates for whole brain and cerebellar layers at various ages. Whole brain succinate semialdehyde dehydrogenase rates were measured at every day of age from birth to 30 days, and less frequently thereafter until day 90. Succinate semialdehyde dehydrogenase was assayed in the layers of the developing rat cerebellum. The data are analysed statistically and correlated with development, dry wt., and total brain protein.

Brain succinate semialdehyde. II. Changes in the developing rat brain.

SUCCINATE semialdehyde dehydrogenase catalyses the terminal step of the y-aminobutyrate pathway which is of significance in mammals only in neural tissues because of the unique localization of the initial catalyst, glutamate decarboxylase AWAPARA, LANDUA, FUERST and SEALE, 1950). The y-aminobutyrate pathway provides both a probable oxidative shunt around a-oxoglutarate dehydrogenase (ROBERTS, 1956) and the source of the potent neural inhibitor y-aminobutyrate (BAZEMORE, ELLIOTT and FLOREY, 1956). An enzymic analytical method for y-aminobutyrate-a-oxoglutarate transaminase (PITTS, QUICK and ROBINS, 1965) is available and demonstrates rates supporting the results of in vivo and in vitro studies with labelled substrates which have demonstrated that as much as half of a-oxoglutarate in brain may be oxidized by the y-aminobutyrate pathway ( MCKHANN, ALBERS, SOKOLOFF, MICHELSEN and TOWER, 1960). ALBERS and SALVADOR (1 958) demonstrated succinate semialdehyde dehydrogenase activities in the range of 3 m-moles per kg protein per hr after 150-fold purification of a particulate fraction from monkey brain. This report is of the measurement of brain succinate semialdehyde dehydrogenase by means of the fluorescence of NADH. The analytical method is sensitive enough to allow assay of succinate semialdehyde dehydrogenase in as little as 0.05 pg freeze-dried brain. Maximal brain succinate semialdehyde dehydrogenase activities are in the range of those of the major metabolic pathways, and specific rates are detailed for various neural regions of several mammalian species. The purification, kinetics and protein characteristics of brain succinate semialdehyde dehydrogenase will be the subjects of subsequent reports.

Brain succinate semialdehyde dehydrogenase—i assay and distribution

—

A systematic study was made of aminobutyrate transaminase (4-aminobutyrate: 2-oxoglutarate aminotransferase, I.U.B.2.6.1.19) in the developing rat brain. Assays of enzymic activity were made in whole brain of seven to twenty-one animals at each day of age from birth to day 30. The numerous analyses allowed statistical treatment and recognition of an abrupt change in the rate of synthesis of aminobutyrate transaminase, as judged by activity/g wet wt., beginning at day 12. From birth through day 11 there was a linear increase of low slope in enzymic activity, from day 12 through day 26 there was a linear increase of markedly increased slope. During the first period γ-aminobutyrate increased from 14 to 25 m-moles/kg fresh wt./hr; during the second the increase was from 25 to 113. The change of slope of linear increase in rat brain aminobutyrate transaminase began abruptly midway in the ‘critical period’ of rat brain development which extends roughly from day 10 to day 14. The onset of peak increase of rat brain succinate semialdehyde dehydrogenase (I.U.B.1.2.1.16) by contrast, occurred at day 6, heralded the ‘critical period’, and preceded by 6 days the onset of peak increase of the transaminase. These time-locked changes in rate of increase of two enzymes of a biochemical pathway uniquely functional in neural tissue may be of significance in determining the development of the nervous system in the young animal.

Brain 4-aminobutyrate

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The enzymic measurement of gamma-aminobutyric-alpha-oxoglutaric transaminase.

Brain succinate semialdehyde. II. Changes in the developing rat brain.

Brain succinate semialdehyde dehydrogenase—i assay and distribution

Brain 4-aminobutyrate