GABA is sold as adietary supplement in many countries. It has been traditionally thought that exogenous GABA (i.e., taken as a supplement) does not cross theblood–brain barrier, but data obtained from more recent research (2010s) in rats describes the notion as being unclear.[4][5]
Neurons that produce GABA as their output are calledGABAergic neurons. In adult vertebrates, GABA is usually considered as the major inhibitory neurotransmitter. It also exhibits excitatory effect via GABAB receptor, in which case, a specific type of voltage dependent calcium channel is activated.[8]
Medium spiny cells are a typical example of inhibitorycentral nervous system GABAergic cells. In contrast, GABA exhibits both excitatory and inhibitory actions ininsects, mediatingmuscle activation at synapses betweennerves and muscle cells, and also the stimulation of certainglands.[9] In mammals, some GABAergic neurons, such aschandelier cells, are also able to excite their glutamatergic counterparts.[10] In addition to fast-acting phasic inhibition, small amounts of extracellular GABA can induce slow timescale tonic inhibition on neurons.[11]
GABAA receptors are ligand-activated chloride channels: when activated by GABA, they allow the flow ofchloride ions across the membrane of the cell.[7] Whether this chloride flow is depolarizing (makes the voltage across the cell's membrane less negative), shunting (has no effect on the cell's membrane potential), or inhibitory/hyperpolarizing (makes the cell's membrane more negative) depends on the direction of the flow of chloride. When net chloride flows out of the cell, GABA is depolarising; when chloride flows into the cell, GABA is inhibitory or hyperpolarizing. When the net flow of chloride is close to zero, the action of GABA is shunting.Shunting inhibition has no direct effect on the membrane potential of the cell; however, it reduces the effect of any coincident synaptic input by reducing theelectrical resistance of the cell's membrane.
Shunting inhibition can "override" the excitatory effect of depolarising GABA, resulting in overall inhibition even if the membrane potential becomes less negative. It was thought that a developmental switch in the molecular machinery controlling the concentration of chloride inside the cell changes the functional role of GABA betweenneonatal and adult stages. As the brain develops into adulthood, GABA's role changes from excitatory to inhibitory.[12]
GABA is an inhibitory transmitter in the mature brain; its actions were thought to be primarily excitatory in the developing brain.[12][13] The gradient of chloride was reported to be reversed in immature neurons, with its reversal potential higher than the resting membrane potential of the cell; activation of a GABA-A receptor thus leads to efflux of Cl− ions from the cell (that is, a depolarizing current). The differential gradient of chloride in immature neurons was shown to be primarily due to the higher concentration of NKCC1 co-transporters relative to KCC2 co-transporters in immature cells. GABAergic interneurons mature faster in the hippocampus and the GABA machinery appears earlier than glutamatergic transmission. Thus, GABA is considered the major excitatory neurotransmitter in many regions of the brain before thematuration ofglutamatergic synapses.[14]
In the developmental stages preceding the formation of synaptic contacts, GABA is synthesized by neurons and acts both as anautocrine (acting on the same cell) andparacrine (acting on nearby cells) signalling mediator.[15][16] Theganglionic eminences also contribute greatly to building up the GABAergic cortical cell population.[17]
mRNA expression of the embryonic variant of the GABA-producing enzymeGAD67 in a coronal brain section of a one-day-oldWistar rat, with the highest expression insubventricular zone (svz)[27]
Besides the nervous system, GABA is also produced at relatively high levels in theinsulin-producingbeta cells (β-cells) of thepancreas. The β-cells secrete GABA along with insulin and the GABA binds to GABA receptors on the neighboringisletalpha cells (α-cells) and inhibits them from secretingglucagon (which would counteract insulin's effects).[28]
GABA can promote the replication and survival of β-cells[29][30][31] and also promote the conversion of α-cells to β-cells, which may lead to new treatments fordiabetes.[32]
Experiments on mice have shown that hypothyroidism induced by fluoride poisoning can be halted by administering GABA. The test also found that the thyroid recovered naturally without further assistance after the fluoride had been expelled by the GABA.[34]
Immune cells express receptors for GABA[35][36] and administration of GABA can suppressinflammatory immune responses and promote "regulatory" immune responses, such that GABA administration has been shown to inhibitautoimmune diseases in several animal models.[29][35][37][38]
In 2018, GABA was shown to regulate secretion of a greater number of cytokines. In plasma ofT1D patients, levels of 26cytokines are increased and of those, 16 are inhibited by GABA in the cell assays.[39]
In 2007, an excitatory GABAergic system was described in the airwayepithelium. The system is activated by exposure to allergens and may participate in the mechanisms ofasthma.[40] GABAergic systems have also been found in thetestis[41] and in the eye lens.[42]
GABA is found mostly as azwitterion (i.e., with thecarboxyl group deprotonated and the amino group protonated). Itsconformation 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 toquantum 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 ofsolvation 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.[43][44]
There was not much further research into the substance until 1957; Canadian researchers identified GABA as the mysterious component (termed Factor I by its discoverers in 1954) of brain andspinal cord extracts which inhibitedcrayfish neurons.[46][48]
In 1959, it was shown that, at aninhibitory synapse on crayfish muscle fibers, GABA acts through stimulation of the inhibitory nerve. Both inhibition by nerve stimulation and by applied GABA are blocked bypicrotoxin.[49]
Historically it was thought that exogenous GABA did not penetrate theblood–brain barrier,[4] but more current research[5] describes the notion as being unclear pending further research.
In general, GABA does not cross theblood–brain barrier,[4] although certain areas of the brain that have no effective blood–brain barrier, such as theperiventricular nucleus, can be reached by drugs such as systemically injected GABA.[58] At least one study suggests that orally administered GABA increases the amount ofhuman growth hormone (HGH).[59] 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.[58] 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.[60]
GABA enhances thecatabolism ofserotonin intoN-acetylserotonin (the precursor ofmelatonin) in rats.[61] It is thus suspected that GABA is involved in the synthesis of melatonin and thus might exert regulatory effects on sleep and reproductive functions.[62]
Although in chemical terms, GABA is anamino 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 aqualifier, refers specifically to analpha amino acid. GABA is not an alpha amino acid, meaning the amino group is not attached to the alpha carbon. Nor is it incorporated intoproteins as are many alpha-amino acids.[63]
GABA is also found in plants.[84][85] It is the most abundant amino acid in theapoplast of tomatoes.[86] Evidence also suggests a role in cell signalling in plants.[87][88] Recently, a new enzyme technology has been developed to enhance the GABA content of protein-rich seeds such as Andean lupine or tarwi (Lupinus mutabilis) and varieties of quinoa (Chenopodium quinoa) and its relative, cañahua (Chenopodium pallidicaule).[89]
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