Synthesis and biological functions of GABA

GABA acts by binding to transmembrane receptors in the plasma membrane of pre- and postsynaptic neurons. Ionotropic and metabotropic receptors are known. The ionotropic GABA-A has binding sites for benzodiazepines, barbiturates, and neurosteroids, in addition to binding sites for GABA. Ιn the pancreas, GABA secreted from β-cells inhibits glucagon secretion from α-cells. GABA also regulates immune responses. GABA exhibits both excitatory and inhibitory actions in insects.

Structure

Molecular formula, C4H9NO2. GABA is an amino acid because it has both amino and carboxyl groups. However, GABA is not an α-amino acid in which amino and carboxyl groups are bound to the same carbon atom.

Properties

Mr 103.12. GABA is soluble in water (～1300mg/mL). GABA is found mostly as a zwitterion with the carboxyl group deprotonated and the amino group protonated in water.

Synthesis and release

Gene, mRNA, and precursor GABA is primarily synthesized from glutamate by glutamate decarboxylase (GAD) and pyridoxal phosphate as a cofactor. GAD exists in two isoforms with molecular weights of 67,000 (GAD1) and 65,000 (GAD2) in mammals, and these are encoded by two different genes.GAD1 and GAD2 are expressed in the brain where GABA is used as a neurotransmitter, and they are also expressed in the insulin-producing β-cells of the pancreas. GAD1 accounts for 80%–90% of overall brain GABA.

Tissue distribution

Although GABA is the chief inhibitory neurotransmitter in the vertebrate CNS, it is also widely distributed in nonneural tissue. GABA exists in the stomach, intestine, ovary, Fallopian tube, uterus, testis, kidney, urinary bladder, lung, and liver at lower levels than the central nervous system and the pancreas.

Biological functions

Target cells/tissues and functions

GABA is the chief inhibitory neurotransmitter in the CNS. Medium spiny neurons, also known as spiny projection neurons, are a special type of GABAergic inhibitory neurons within the human striatum. In the developing brain, GABA regulates the proliferation of neural progenitor cells, migration, the differentiation of neurites, and the formation of synapses. GABA is considered to be the major excitatory neurotransmitter before thematuration of glutamatergic synapses and regulates the growth of embryonic and neural stem cells. β-cells in the pancreas secrete GABA along with insulin. GABA binds to GABA receptors on the islet α-cells and inhibits glucagon secretion.GABA promotes the replication and survival of β-cells16 and the conversion of α-cells to β-cells.Immune cells express GABA receptors and GABA can suppressinflammatoryimmune responses. GABA exerts both excitatory and inhibitory actions in insects at synapses between nerves and muscles as well as certain glands.

Phenotype of gene-modified animals

The effect of GABAergic input deprivation on inhibitory terminal formation was investigated in Purkinje cell-specific vesicular GABA transporter (VGAT) knockout mice, in which the GABA release from Purkinje cells diminishes in an age-dependent manner. The results suggested that the deprivation of GABAergic inputs from Purkinje cells accelerates the formation of coreleasing terminals derived from interneurons and that the inhibitory terminal numbers and types are regulated by the quantity of functional GABAergic inputs.

Clinical implications

GABA has both stimulatory and inhibitory effects on the production of growth hormone, depending on the physiology of the individual.GABA increased the conversion of serotonin into N-acetylserotonin, the precursor of melatonin, in rats.

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