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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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GABA Synthesis, Uptake and Release

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GABA is formed in vivo by a metabolic pathway referred to as the GABA shunt

The GABA shunt is a closed-loop process with the dual purpose of producing and conserving the supply of GABA. GABA is present in high concentrations (millimolar) in many brain regions. These concentrations are about 1,000 times higher than concentrations of the classical monoamine neurotransmitters in the same regions. This is in accord with the powerful and specific actions of GABAergic neurons in these regions. Glucose is the principal precursor for GABA production in vivo, although pyruvate and other amino acids also can act as precursors. The first step in the GABA shunt is the transamination of α-ketoglutarate, formed from glucose metabolism in the Krebs cycle by GABA α-oxoglutarate transaminase (GABA-T) into l-glutamic acid [4] (Fig. 16-1). Glutamic acid decarboxylase (GAD) catalyzes the decarboxylation of glutamic acid to form GABA. GAD appears to be expressed only in cells that use GABA as a neurotransmitter. GAD, localized with antibodies or mRNA hybridization probes, serves as an excellent marker for GABAergic neurons in the CNS. Two related but different genes for GAD have been cloned, suggesting independent regulation and properties for the two forms of GAD: GAD65 and GAD67. Furthermore, expression of GAD and some GABA receptor subunits has been demonstrated in some non-neural tissues, indicating the likely function of GABA outside of the CNS [5]. GABA is metabolized by GABA-T to form succinic semialdehyde. To conserve the available supply of GABA, this transamination generally occurs when the initial parent compound, α-ketoglutarate, is present to accept the amino group removed from GABA, reforming glutamic acid. Therefore, a molecule of GABA can be metabolized only if a molecule of precursor is formed. Succinic semialdehyde can be oxidized by succinic semialdehyde dehydrogenase (SSADH) into succinic acid and can then reenter the Krebs cycle, completing the loop.

Figure 16-1. GABA shunt reactions are responsible for the synthesis, conservation and metabolism of GABA.

Figure 16-1

GABA shunt reactions are responsible for the synthesis, conservation and metabolism of GABA. GABA-T, GABA α-oxoglutarate transaminase; GAD, glutamic acid decarboxylase; SSADH, succinic semialdehyde dehydrogenase.

GABA release into the synaptic cleft is stimulated by depolarization of presynaptic neurons. GABA diffuses across the cleft to the target receptors on the postsynaptic surface. The action of GABA at the synapse is terminated by reuptake into both presynaptic nerve terminals and surrounding glial cells. The membrane transport systems mediating reuptake of GABA are both temperature- and ion-dependent processes. These transporters are capable of bidirectional neurotransmitter transport. They have an absolute requirement for extracellular Na+ ions with an additional dependence on Cl ions. The ability of the reuptake system to transport GABA against a concentration gradient has been demonstrated using synaptosomes. Under normal physiological conditions, the ratio of internal to external GABA is about 200. The driving force for this reuptake process is supplied by the movement of Na+ down its concentration gradient [6] (see Chap. 5). GABA taken back up into nerve terminals is available for reutilization, but GABA in glia is metabolized to succinic semialdehyde by GABA-T and cannot be resynthesized in this compartment since glia lack GAD. Ultimately, GABA can be recovered from this source by a circuitous route involving the Krebs cycle [4]; GABA in glia is converted to glutamine, which is transferred back to the neuron, where glutamine is converted by glutaminase to glutamate, which re-enters the GABA shunt (see Chap. 15).

The family of GABA transporters is a set of 80-kDa glycoproteins with multiple transmembrane regions; they have no sequence homology with GABA receptors. Pharmacological and kinetic studies have suggested a variety of subtypes, and at least six separate but related entities have been demonstrated by molecular cloning [6,7]. This has led to rapid developments in understanding the localization, pharmacological specificity, structure—function and mechanism of GABA transport.

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Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK27979


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