GABA

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GABA (gamma-aminobutyric acid, 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.

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 (2010s) in rats describes the notion as being unclear.<ref name="Kuriyama" /><ref name=":1" />

The carboxylate form of GABA is γ-aminobutyrate.

FunctionEdit

NeurotransmitterEdit

Two general classes of GABA receptor are known:<ref>Template:Cite book</ref>

GABA_A in which the receptor is part of a ligand-gated ion channel complex<ref name="elifesciences.org">Template:Cite journal</ref>
GABA_B metabotropic receptors, which are G protein-coupled receptors that open or close ion channels via intermediaries (G proteins)

File:Release, Reuptake, and Metabolism Cycle of GABA.png

Release, reuptake, and metabolism cycle of GABA

Neurons that produce GABA as their output are called GABAergic neurons, and have chiefly inhibitory action at receptors in the adult vertebrate. Medium spiny cells are a typical example of inhibitory central nervous system GABAergic cells. In contrast, GABA exhibits both excitatory and inhibitory actions in insects, mediating muscle activation at synapses between nerves and muscle cells, and also the stimulation of certain glands.<ref name="pmid8389005">Template:Cite journal</ref> In mammals, some GABAergic neurons, such as chandelier cells, are also able to excite their glutamatergic counterparts.<ref name="pmid16410524">Template:Cite journal</ref> In addition to fast-acting phasic inhibition, small amounts of extracellular GABA can induce slow timescale tonic inhibition on neurons.<ref name="Koh Kwak Cheong Lee 2023">Template:Cite journal</ref>

GABA_A receptors are ligand-activated chloride channels: when activated by GABA, they allow the flow of chloride ions across the membrane of the cell.<ref name="elifesciences.org"/> 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 the electrical 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 between neonatal and adult stages. As the brain develops into adulthood, GABA's role changes from excitatory to inhibitory.<ref name="pmid18500393">Template:Cite journal</ref>

Brain developmentEdit

GABA is an inhibitory transmitter in the mature brain; its actions were thought to be primarily excitatory in the developing brain.<ref name="pmid18500393"/><ref name="pmid17928584">Template:Cite journal</ref> 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 the maturation of glutamatergic synapses.<ref>Template:Cite book</ref>

In the developmental stages preceding the formation of synaptic contacts, GABA is synthesized by neurons and acts both as an autocrine (acting on the same cell) and paracrine (acting on nearby cells) signalling mediator.<ref name="isbn0-87893-697-1">Template:Cite book</ref><ref name="pmid16512345">Template:Cite book</ref> The ganglionic eminences also contribute greatly to building up the GABAergic cortical cell population.<ref name="pmid11715055">Template:Cite journal</ref>

GABA regulates the proliferation of neural progenitor cells,<ref name="pmid8845153">Template:Cite journal</ref><ref name="pmid10908617">Template:Cite journal</ref> the migration<ref name="pmid9698329">Template:Cite journal</ref> and differentiation<ref name="pmid11371348">Template:Cite journal</ref><ref name="pmid8390627">Template:Cite journal</ref> the elongation of neurites<ref name="pmid11264309">Template:Cite journal</ref> and the formation of synapses.<ref name="pmid12209121">Template:Cite journal</ref>

GABA also regulates the growth of embryonic and neural stem cells. GABA can influence the development of neural progenitor cells via brain-derived neurotrophic factor (BDNF) expression.<ref name="pmid12163549">Template:Cite journal</ref> GABA activates the GABA_A receptor, causing cell cycle arrest in the S-phase, limiting growth.<ref name="pmid18852839">Template:Cite journal</ref>

Beyond the nervous systemEdit

File:Autoradiography of a brain slice from an embryonal rat - PMID19190758 PLoS 0004371.png

mRNA expression of the embryonic variant of the GABA-producing enzyme GAD67 in a coronal brain section of a one-day-old Wistar rat, with the highest expression in subventricular zone (svz)<ref name="pmid19190758">Template:Cite journal</ref>

Besides the nervous system, GABA is also produced at relatively high levels in the insulin-producing beta cells (β-cells) of the pancreas. The β-cells secrete GABA along with insulin and the GABA binds to GABA receptors on the neighboring islet alpha cells (α-cells) and inhibits them from secreting glucagon (which would counteract insulin's effects).<ref name="pmid2550826">Template:Cite journal</ref>

GABA can promote the replication and survival of β-cells<ref name="pmid21709230">Template:Cite journal</ref><ref name="pmid23995958">Template:Cite journal</ref><ref name="pmid25008178">Template:Cite journal</ref> and also promote the conversion of α-cells to β-cells, which may lead to new treatments for diabetes.<ref name="pmid27916274">Template:Cite journal</ref>

Alongside GABAergic mechanisms, GABA has also been detected in other peripheral tissues including intestines, stomach, fallopian tubes, uterus, ovaries, testicles, kidneys, urinary bladder, the lungs and liver, albeit at much lower levels than in neurons or β-cells.<ref name="pmid2405103">Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

Immune cells express receptors for GABA<ref name="pmid10227421">Template:Cite journal</ref><ref name="pmid22927941">Template:Cite journal</ref> and administration of GABA can suppress inflammatory immune responses and promote "regulatory" immune responses, such that GABA administration has been shown to inhibit autoimmune diseases in several animal models.<ref name="pmid21709230"/><ref name="pmid10227421"/><ref name="pmid15470076">Template:Cite journal</ref><ref name="pmid21604972">Template:Cite journal</ref>

In 2018, GABA was shown to regulate secretion of a greater number of cytokines. In plasma of T1D patients, levels of 26 cytokines are increased and of those, 16 are inhibited by GABA in the cell assays.<ref>Template:Cite journal</ref>

In 2007, an excitatory GABAergic system was described in the airway epithelium. The system is activated by exposure to allergens and may participate in the mechanisms of asthma.<ref name="GABA_lungs">Template:Cite journal</ref> GABAergic systems have also been found in the testis<ref name="Inyerballs">Template:Cite book</ref> and in the eye lens.<ref name="GABA_lens">Template:Cite journal</ref>

Structure and conformationEdit

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.<ref name="Majumdar Guha 1988">Template:Cite journal</ref><ref>Template:Cite book Template:Page needed</ref>

HistoryEdit

GABA was first synthesized in 1883; it was first known only as a plant and microbe metabolic product.<ref name="isbn0-19-514008-7">Template:Cite book</ref>

In 1950, Washington University School of Medicine researchers Eugene Roberts and Sam Frankel used newly-developed techniques of chromatography to analyze protein-free extracts of mammalian brain. They discovered that GABA is metabolized from glutamic acid and accumulates in the mammalian central nervous system.<ref name=":2">Template:Cite journal</ref><ref>Template:Cite journal</ref>

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 and spinal cord extracts which inhibited crayfish neurons.<ref name=":2" /><ref>Template:Cite journal</ref>

In 1959, it was shown that, at an inhibitory synapse on crayfish muscle fibers, GABA acts through stimulation of the inhibitory nerve. Both inhibition by nerve stimulation and by applied GABA are blocked by picrotoxin.<ref>Template:Cite journal</ref>

BiosynthesisEdit

File:Gabaergic Neurons.png

GABAergic neurons which produce GABA

GABA is primarily synthesized from glutamate via the enzyme glutamate decarboxylase (GAD) with pyridoxal phosphate (the active form of vitamin B6) as a cofactor. This process converts glutamate (the principal excitatory neurotransmitter) into GABA (the principal inhibitory neurotransmitter).<ref name="pmid12467378">Template:Cite journal</ref><ref name="pmid17499106">Template:Cite conference</ref>

GABA can also be synthesized from putrescine<ref name=":0">Template:Cite journal</ref><ref>Template:Cite journal</ref> by diamine oxidase and aldehyde dehydrogenase.<ref name=":0" />

Historically it was thought that exogenous GABA did not penetrate the blood–brain barrier,<ref name=Kuriyama>Template:Cite journal</ref> but more current research<ref name=":1">Template:Cite journal</ref> describes the notion as being unclear pending further research.

MetabolismEdit

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.<ref name=catabolism>Template:Cite journal</ref>

PharmacologyEdit

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).<ref name="pmid16377242">Template:Cite journal</ref><ref name="pmid11583788">Template:Cite journal</ref> Many of the substances below are known to cause anterograde amnesia and retrograde amnesia.<ref name="pmid12761368">Template:Cite journal</ref>

In general, GABA does not cross the blood–brain barrier,<ref name="Kuriyama"/> 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.<ref name=Muller1999/> At least one study suggests that orally administered GABA increases the amount of human growth hormone (HGH).<ref name=Powers2008>Template:Cite journal</ref> 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.<ref name="Muller1999">Template:Cite journal</ref> 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.<ref name="pmid34444905">Template:Cite journal</ref>

GABA enhances the catabolism of serotonin into N-acetylserotonin (the precursor of melatonin) in rats.<ref name="pmid6844712">Template:Cite journal</ref> It is thus suspected that GABA is involved in the synthesis of melatonin and thus might exert regulatory effects on sleep and reproductive functions.<ref>Template:Cite journal</ref>

ChemistryEdit

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.<ref>Template:Cite book</ref>

GABAergic drugsEdit

GABA_A receptor ligands are shown in the following table.Template:Refn

Activity at GABA_A	Ligand
Orthosteric agonist	Muscimol,<ref name="pmid28528665">Template:Cite book</ref> GABA,<ref name="pmid28528665"/> gaboxadol (THIP),<ref name="pmid28528665"/> isoguvacine, progabide, piperidine-4-sulfonic acid (partial agonist)
Positive allosteric modulators	Barbiturates,<ref name="Loescher&Rogawski">Template:Cite journal</ref> benzodiazepines,<ref name="isbn0-12-088397-X">Template:Cite book</ref> neuroactive steroids,<ref name="neuroactive_steroid">Template:Multiref2</ref> niacin/niacinamide,<ref>Template:Cite journal</ref> nonbenzodiazepines (i.e., z-drugs, e.g., zolpidem), etomidate,<ref>Template:Cite conference</ref> alcohol (ethanol),<ref name="pmid12692303">Template:Cite journal</ref><ref name="pmid9311780">Template:Cite journal</ref><ref name="pmid17175815">Source unclear. One of the following: Template:Cite journal Template:Cite book</ref> methaqualone, propofol, stiripentol,<ref>Template:Cite journal</ref> and anaesthetics<ref name="pmid28528665"/> (including volatile anaesthetics)
Orthosteric (competitive) antagonist	bicuculline,<ref name="pmid28528665"/> gabazine,<ref>Template:Cite journal</ref> thujone,<ref>Template:Cite journal</ref> flumazenil<ref>Template:Cite journal</ref>
Uncompetitive antagonist (e.g., channel blocker)	cicutoxin
Negative allosteric modulators	furosemide, oenanthotoxin, amentoflavone

GABAergic pro-drugs include chloral hydrate, which is metabolised to trichloroethanol,<ref name=Ull>Template:Ullmann</ref> which then acts via the GABA_A receptor.<ref>Template:Cite journal</ref>

The plant kava contains GABAergic compounds, including kavain, dihydrokavain, methysticin, dihydromethysticin and yangonin.<ref name="pmid12383029">Template:Cite journal</ref>

Template:More medical citations needed Other GABAergic modulators include:

GABA_B receptor ligands.Template:Citation needed
- Agonists: baclofen, propofol, GHB,<ref name="pmid16129424">Template:Cite journal</ref> phenibut.
- Antagonists: phaclofen, saclofen.
GABA reuptake inhibitors: deramciclane, hyperforin, tiagabine.Template:Citation needed
GABA transaminase inhibitors: gabaculine, phenelzine, valproate, vigabatrin, lemon balm (Melissa officinalis).<ref name="pmid19165747">Template:Cite journal</ref>
GABA analogues: pregabalin, gabapentin,<ref name="pmid21296127">Template:Cite journal</ref> picamilon, progabide Template:Citation needed

4-Amino-1-butanol is a biochemical precursor of GABA and can be converted into GABA by the actions of aldehyde reductase (ALR) and aldehyde dehydrogenase (ALDH) with γ-aminobutyraldehyde (GABAL) as a metabolic intermediate.<ref name="StorerFerrante1997">Template:Cite book</ref>

In plantsEdit

GABA is also found in plants.<ref name="pmid26219411">Template:Cite journal</ref><ref name="pmid27838745">Template:Cite journal</ref> It is the most abundant amino acid in the apoplast of tomatoes.<ref>Template:Cite journal</ref> Evidence also suggests a role in cell signalling in plants.<ref name="pmid15003233">Template:Cite journal</ref><ref name="pmid19704616">Template:Cite journal</ref> 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). <ref>Template:Cite journal</ref>

NotesEdit

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ReferencesEdit