γ-Aminobutyric acid

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(Redirected from
GABA neurotransmitter
)
"GABA" redirects here. For other uses, see Gaba (disambiguation).
γ-Aminobutyric acid
Simplified structural formula
GABA molecule
Names
Preferred IUPAC name
4-Aminobutanoic acid
Other names
γ-Aminobutanoic acid
4-Aminobutyric acid
3-Carboxypropylamine
Piperidic acid
Piperidinic acid
Identifiers
3D model (
JSmol
)
906818
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard
 100.000.235 Edit this at Wikidata
EC Number
  • 200-258-6
49775
IUPHAR/BPS
KEGG
MeSH gamma-Aminobutyric+Acid
RTECS number
  • ES6300000
UNII
  • InChI=1S/C4H9NO2/c5-3-1-2-4(6)7/h1-3,5H2,(H,6,7) checkY
    Key: BTCSSZJGUNDROE-UHFFFAOYSA-N checkY
  • InChI=1/C4H9NO2/c5-3-1-2-4(6)7/h1-3,5H2,(H,6,7)
    Key: BTCSSZJGUNDROE-UHFFFAOYAC
  • NCCCC(=O)O
Properties
C4H9NO2
Molar mass 103.121 g·mol−1
Appearance white microcrystalline powder
Density 1.11 g/mL
Melting point 203.7 °C (398.7 °F; 476.8 K)
Boiling point 247.9 °C (478.2 °F; 521.0 K)
130 g/100 ml
log P −3.17
Acidity (pKa)
  • 4.031 (carboxyl; H2O)
  • 10.556 (amino; H2O)[1]
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
 Irritant, Harmful
Lethal dose or concentration (LD, LC):
12,680 mg/kg (mouse, oral)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

γ-Aminobutyric acid (gamma-aminobutyric acid)

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 in rats describes the notion as being unclear.[2][3]

The carboxylate form of GABA is γ-aminobutyrate.

Function

Neurotransmitter

Two general classes of GABA receptor are known:[4]

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.[6] In mammals, some GABAergic neurons, such as chandelier cells, are also able to excite their glutamatergic counterparts.[7] In addition to fast-acting phasic inhibition, small amounts of extracellular GABA can induce slow timescale tonic inhibition on neurons.[8]

neonatal and adult stages. As the brain develops into adulthood, GABA's role changes from excitatory to inhibitory.[9]

Brain development

GABA is an inhibitory transmitter in the mature brain; its actions were thought to be primarily excitatory in the developing brain.

glutamatergic synapses.[11]

In the developmental stages preceding the formation of synaptic contacts, GABA is synthesized by neurons and acts both as an

paracrine (acting on nearby cells) signalling mediator.[12][13] The ganglionic eminences also contribute greatly to building up the GABAergic cortical cell population.[14]

GABA regulates the proliferation of neural progenitor cells,[15][16] the migration[17] and differentiation[18][19] the elongation of neurites[20] and the formation of synapses.[21]

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.[22] GABA activates the GABAA receptor, causing cell cycle arrest in the S-phase, limiting growth.[23]

Beyond the nervous system

GAD67 in a coronal brain section of a one-day-old Wistar rat, with the highest expression in subventricular zone (svz)[24]

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).[25]

GABA can promote the replication and survival of β-cells[26][27][28] and also promote the conversion of α-cells to β-cells, which may lead to new treatments for diabetes.[29]

Alongside GABAergic mechanisms, GABA has also been detected in other peripheral tissues including intestines, stomach,

lungs and liver, albeit at much lower levels than in neurons or β-cells.[30]

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.[31]

Immune cells express receptors for GABA[32][33] 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.[26][32][34][35]

In 2018, GABA has 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.[36]

In 2007, an excitatory GABAergic system was described in the airway

testis[38] and in the eye lens.[39]

Structure and conformation

GABA is found mostly as a

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

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]

Biosynthesis

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).[44][45]

GABA can also be synthesized from putrescine[46][47] by diamine oxidase and aldehyde dehydrogenase.[46]

Historically it was thought that exogenous GABA did not penetrate the blood–brain barrier,[2] but more current research[3] describes the notion as being unclear pending further research.

Metabolism

succinic semialdehyde dehydrogenase and as such enters the citric acid cycle as a usable source of energy.[48]

Pharmacology

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

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

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

Although in chemical terms, GABA is an

proteins as are many alpha-amino acids.[58]

GABAergic drugs

GABAA receptor ligands are shown in the following table[nb 1]

Activity at GABAA Ligand
Orthosteric Agonist
THIP),[59] isoguvacine, progabide
, piperidine-4-sulfonic acid (partial agonist)
Positive allosteric modulators
volatile anaesthetics
)
Orthosteric (competitive) Antagonist bicuculline,[59] gabazine,[69] thujone,[70] flumazenil[71]
Uncompetitive antagonist
(e.g., channel blocker) 		cicutoxin
Negative allosteric modulators furosemide, oenanthotoxin, amentoflavone

GABAergic pro-drugs include

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:

In plants

GABA is also found in plants.[78][79] It is the most abundant amino acid in the apoplast of tomatoes.[80] Evidence also suggests a role in cell signalling in plants.[81][82]

See also

Notes

  1. ^ Many more GABAA ligands are listed at Template:GABA receptor modulators and at GABAA receptor#Ligands

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