gABA
GABA (γ-Aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system.
For other uses, see Gaba (disambiguation).
GABA is sold as a dietary supplement in many countries. It has been traditionally thought that exogenous GABA (i.e., taken as a supplement) does not cross the blood–brain barrier, but data obtained from more recent research in rats describes the notion as being unclear.[2][3]
The carboxylate form of GABA is γ-aminobutyrate.
Function[edit]
Neurotransmitter[edit]
Two general classes of GABA receptor are known:[4]
Structure and conformation[edit]
GABA is found mostly as a zwitterion (i.e., with the carboxyl group deprotonated and the amino group protonated). Its conformation depends on its environment. In the gas phase, a highly folded conformation is strongly favored due to the electrostatic attraction between the two functional groups. The stabilization is about 50 kcal/mol, according to quantum chemistry calculations. In the solid state, an extended conformation is found, with a trans conformation at the amino end and a gauche conformation at the carboxyl end. This is due to the packing interactions with the neighboring molecules. In solution, five different conformations, some folded and some extended, are found as a result of solvation effects. The conformational flexibility of GABA is important for its biological function, as it has been found to bind to different receptors with different conformations. Many GABA analogues with pharmaceutical applications have more rigid structures in order to control the binding better.[40][41]
History[edit]
In 1883, GABA was first synthesized, and it was first known only as a plant and microbe metabolic product.[42]
In 1950, GABA was discovered as an integral part of the mammalian central nervous system.[42]
In 1959, it was shown that at an inhibitory synapse on crayfish muscle fibers GABA acts like stimulation of the inhibitory nerve. Both inhibition by nerve stimulation and by applied GABA are blocked by picrotoxin.[43]
Metabolism[edit]
GABA transaminase enzymes catalyze the conversion of 4-aminobutanoic acid (GABA) and 2-oxoglutarate (α-ketoglutarate) into succinic semialdehyde and glutamate. Succinic semialdehyde is then oxidized into succinic acid by succinic semialdehyde dehydrogenase and as such enters the citric acid cycle as a usable source of energy.[48]
Pharmacology[edit]
Drugs that act as allosteric modulators of GABA receptors (known as GABA analogues or GABAergic drugs), or increase the available amount of GABA, typically have relaxing, anti-anxiety, and anti-convulsive effects (with equivalent efficacy to lamotrigine based on studies of mice).[49][50] Many of the substances below are known to cause anterograde amnesia and retrograde amnesia.[51]
In general, GABA does not cross the blood–brain barrier,[2] although certain areas of the brain that have no effective blood–brain barrier, such as the periventricular nucleus, can be reached by drugs such as systemically injected GABA.[52] At least one study suggests that orally administered GABA increases the amount of human growth hormone (HGH).[53] GABA directly injected to the brain has been reported to have both stimulatory and inhibitory effects on the production of growth hormone, depending on the physiology of the individual.[52] Consequently, considering the potential biphasic effects of GABA on growth hormone production, as well as other safety concerns, its usage is not recommended during pregnancy and lactation.[54]
GABA enhances the catabolism of serotonin into N-acetylserotonin (the precursor of melatonin) in rats.[55] It is thus suspected that GABA is involved in the synthesis of melatonin and thus might exert regulatory effects on sleep and reproductive functions.[56]
Research has indicated that oral supplementation of GABA does not yield any favorable outcomes in terms of stress reduction and enhancement of sleep quality in human subjects.[57]
Chemistry[edit]
Although in chemical terms, GABA is an amino acid (as it has both a primary amine and a carboxylic acid functional group), it is rarely referred to as such in the professional, scientific, or medical community. By convention the term "amino acid", when used without a qualifier, refers specifically to an alpha amino acid. GABA is not an alpha amino acid, meaning the amino group is not attached to the alpha carbon. Nor is it incorporated into proteins as are many alpha-amino acids.[58]
GABAA receptor ligands are shown in the following table[nb 1]
GABAergic pro-drugs include chloral hydrate, which is metabolised to trichloroethanol,[72] which then acts via the GABAA receptor.[73]
The plant kava contains GABAergic compounds, including kavain, dihydrokavain, methysticin, dihydromethysticin and yangonin.[74]
Other GABAergic modulators include: