γ-Aminobutyric acid, also known as GABA (gamma-aminobutyric acid) for short, is a biogenic amine of glutamic acid. At the same time, GABA is the major inhibitory neurotransmitter in the central nervous system (CNS).
What is γ-aminobutyric acid?
γ-Aminobutyric acid is a derivative of glutamic acid and an amine of butyric acid. Amines are organic derivatives of ammonia in which one or more hydrogen atoms are replaced by alkyl groups or by aryl groups. Chemically, γ-aminobutyric acid is a nonproteinogenic amino acid. Non-proteinogenic amino acids are amino acids that are not incorporated into proteins during translation. They act as amino acid antagonists in enzyme metabolism in the body. The γ-aminobutyric acid differs from the other proteinogenic α-amino acids by its position of the amino group. GABA is a γ-amino acid because its amino group is located at the third carbon atom after the carboxyl carbon atom. GABA binds to specific receptors in the body. It acts as an inhibitory (inhibitory) neurotransmitter in the body.
Function, effects, and roles
GABA exerts its effects at various receptors in the body. GABAa receptors are ligand-gated cloridione channels. When GABA binds to the receptor, chloride flows in. This has an inhibitory effect on the affected nerve cell. GABAa receptors are widely distributed in the brain. They play an important role in the balance between attenuation and excitation in the central nervous system. Several drugs that have a depressant effect act at the GABAa receptor. These agents include benzodiazepines, antiepileptic drugs, propofol, and barbiturates. GABAa-ρ receptors have a similar effect to GABAa receptors. However, they cannot be affected by the drugs mentioned above. GABAb receptors are so-called G-protein-coupled receptors. When γ-aminobutyric acid binds to these receptors, increased potassium flows into the nerve cell. At the same time, there is a reduced outflow of calcium. Thus, presynaptic hyperpolarization and inhibition of transmitter release occur. Behind the synaptic cleft, on the other hand, there is an increased influx of potassium. As a result, an inhibitory postsynaptic potential (IPSP) develops. The muscle relaxant baclofen acts precisely at this receptor. Generally speaking, GABA has antianxiety, analgesic, relaxant, anticonvulsant, and blood pressure stabilizing effects. In addition, GABA has a sleep-promoting effect. However, GABA does not only act as an inhibitory neurotransmitter. GABA also inhibits hormone secretion in various endocrine glands. A significant effect is exerted by γ-aminobutyric acid in the pancreas. There, the acid inhibits the secretion of glucagon in the alpha cells of the islets of Langerhans. However, GABA also acts centrally on the hypothalamus and thus on the secretion of releasing hormones. GABAergic neurons also supply the pituitary gland, so that the pituitary production of prolactin, ACTH, TSH and LH is also influenced by GABA. GABA also stimulates hypothalamic HGH-releasing hormone. In addition, γ-aminobutyric acid is thought to have an immunomodulatory effect. Via GABA receptors located on T cells, γ-aminobutyric acid blocks the secretion of proinflammatory cytokines while inhibiting the activation and proliferation of T cells.
Formation, occurrence, properties, and optimal levels
γ-Aminobutyric acid is formed from glutamate. This requires the enzyme glutamate decarboxylase (GAD). Glutamate is the major excitatory neurotransmitter. By only one step, the effect is almost reversed and an inhibitory neurotransmitter is formed. Immediately after formation, some γ-aminobutyric acid is transported to the neighboring glial cells. There, GABA can be converted to succinate semialdehyde by GABA transaminase. It can thus be incorporated into the citrate cycle and degraded. In the pancreas, GABA is produced in the insulin-producing beta cells of the islets of Langerhans. GABA is formed from glutamate by the enzyme GAD65. The secretion takes place on the one hand via SLMV. SLMV are synaptic-like microvesicles that resemble synaptic vesicles. However, over a small portion, GABA is also secreted in the pancreas via LDCV, the so-called large dense core vesicles. These vesicles contain a typical complex of insulin and zinc. The respective vesicles have a GABA transporter.GABA secretion in the pancreas occurs every four hours. In addition, vesicular secretion occurs.
Diseases and disorders
Low levels of γ-aminobutyric acid are regularly found in various diseases. These include, for example, chronic pain, hypertension, irritable colon, premenstrual syndrome (PMS), depression, schizophrenia, and epilepsy. Deficiency of γ-aminobutyric acid can cause night sweats, impulsivity, anxiety, and memory impairment. Impatience, rapid heartbeat, ringing in the ears (tinnitus), cravings for sweets, and muscle tension are also symptoms of GABA deficiency. A GABA deficiency can be treated in different ways. For example, those affected can take the GABA precursor glutamine. Likewise, treatment can be done in combination with the small amino acid glycine. However, oral administration of GABA mainly affects the periphery, i.e., the endocrine organs and tissues. A central effect cannot be achieved because the blood–brain barrier impedes the uptake of γ-aminobutyric acid. However, γ-aminobutyric acid can also be overdosed. Combination with benzodiazepines, alcohol, antipsychotics, hypnotics, anesthetics, tricyclic antidepressants, opioids, and muscle relaxants is particularly dangerous. They may increase the effects and side effects of γ-aminobutyric acid. Overdose of γ-aminobutyric acid may cause dizziness and muscle weakness. Sufferers experience somnolence and slowed heartbeat. They feel weak, have respiratory depression, seizures, and suffer from memory loss. When γ-aminobutyric acid is combined with other central nervous substances, life-threatening cardiac arrest can occur. GABA also appears to play a role in the pathophysiology of diabetes mellitus. Thus, increased glucagon formation in diabetics is thought to be caused by GABA deficiency. In addition, T lymphocyte activity appears to be decreased mediated by GABA.
