GABA

GABA, gamma-aminobutyric acid, an amine of butyric acid, is a non-proteinogenic amino acid (the position of the amino group on the gamma carbon atom with respect to the carboxy group distinguishes it from the proteinogenic alpha-amino acids), with the molecular formula C4H9NO2. GABA is found in almost all prokaryotic and eukaryotic organisms. GABA is the major inhibitory neurotransmitter in the CNS. Approximately 17-20% of all neurons in the brain are GABAergic. GABA activates ionotropic and metabotropic receptors; furthermore, GABA passes membranes via plasmalemmal trasnporters (GAT) and vesicular transporters (VGAT) and is a substrate of transaminase.

Role of GABA in the pancreas: GABA acts as an inhibitory transmitter in the pancreas by inhibiting glucagon secretion from alpha cells in the islets of Langerhans.

Formation of GABA: GABA is catalytically formed from glutamate via the cytosolic enzyme glutamic acid decarboxylase (GAD). This enzyme is expressed in the CNS only in GABAergic neurons. Glutamate is formed from glutamine, which is converted to glutamate after uptake in GABAergic neurons. However, glutamate can also be formed from alpha-ketoglutarate in the mitochondria of GABAergic neurons. GABA is stored in vesicular storage vesicles. This is done by a vesicular GABA transporter. Release of GABA into the synaptic cleft occurs by exocytosis.

Inactivation of GABA: Inactivation of GABA from the synaptic cleft occurs through GBA transporters. Thus, the neuronal GABA transporter (GAT-1) mediates reuptake into the neuron. The absorbed GABA is either stored back into vesicles or enzymatically degraded in 2 steps.

The degradation is carried out by the enzyme GABA transaminase. This enzyme catalyzes the conversion of 4-aminobutyric acid and 2-oxoglutarate to succinate semialdehyde and glutamate. Succinate semialdehyde is subsequently oxidized by succinate semialdehyde dehydrogenase to succinic acid, which enters the citrate cycle as a member of the citrate cycle and is converted back to glutamate via an intermediate step. Glutamate can then be used to synthesize GABA again by decarboxylation, which in turn is taken up from the axoplasm (axoplasm is the term used to describe the portion of cytoplasm localized within the axon of a neuron) into the salivary vesicles. (Aktories et al. 2009).

Postsynaptically, other GABA transporters are responsible for the cellular uptake of GABA. In contrast, intracellular metabolism in the postsynaptic cell is analogous to the presynaptic side.

With the synthesis of GABA, an inhibitory neurotransmitter (GABA) is formed in one step from an excitatory neurotransmitter (glutamate).

GABA modulators: For basic research, the plant toxins picrotoxin of false myrtle and bicuculline of cordial are used as GABA antagonists in addition to the synthetic agent gabazine. Muscimol, one of the poisons of the fly agaric, is relevant as a GABA agonist.

As agonist in the medical application serves the active substance Baclofen.

1. Graefe KH et al. (2016) Physiological principles. In: Graefe KH et al (Eds) Pharmacology and Toxicology. Georg Thieme Verlag Stuttgart pp 273-275.
2. Jorgensen EM (2005) GABA. Worm Book 31:1-13.
3. Roth FC et al (2012) GABA metabolism and transport: effects on synaptic efficacy. Neural Plast 2012:805830.