||This article needs more medical references for verification or relies too heavily on primary sources. (June 2015)|
|Molar mass||103.120 g/mol|
|Appearance||white microcrystalline powder|
|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|
|Acidity (pKa)||4.23 (carboxyl), 10.43 (amino)|
|Main hazards||Irritant, Harmful|
|Lethal dose or concentration (LD, LC):|
LD50 (Median dose)
|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).
|what is: / ?)(|
γ-Aminobutyric acid (/ /; or GABA //) is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays the principal role in reducing neuronal excitability throughout the nervous system. In humans, GABA is also directly responsible for the regulation of muscle tone.
Although in chemical terms it is an amino acid, GABA is rarely referred to as such in the scientific or medical communities, because the term "amino acid," used without a qualifier, by convention refers to the alpha amino acids, which GABA is not, nor is it considered to be incorporated into proteins.
In spastic diplegia in humans, GABA absorption becomes impaired by nerves damaged from the condition's upper motor neuron lesion, which leads to hypertonia of the muscles signaled by those nerves that can no longer absorb GABA.
In vertebrates, GABA acts at inhibitory synapses in the brain by binding to specific transmembrane receptors in the plasma membrane of both pre- and postsynaptic neuronal processes. This binding causes the opening of ion channels to allow the flow of either negatively charged chloride ions into the cell or positively charged potassium ions out of the cell. This action results in a negative change in the transmembrane potential, usually causing hyperpolarization. Two general classes of GABA receptor are known: GABAA in which the receptor is part of a ligand-gated ion channel complex, and GABAB metabotropic receptors, which are G protein-coupled receptors that open or close ion channels via intermediaries (G proteins).
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 CNS 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. In mammals, some GABAergic neurons, such as chandelier cells, are also able to excite their glutamatergic counterparts.
GABAA receptors are ligand-activated chloride channels; that is, when activated by GABA, they allow the flow of chloride ions across the membrane of the cell. Whether this chloride flow is excitatory/depolarizing (makes the voltage across the cell's membrane less negative), shunting (has no effect on the cell's membrane) 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 excitatory or depolarizing; when the net 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 minimizes the effect of any coincident synaptic input essentially by reducing the electrical resistance of the cell's membrane (in essence, equivalent to Ohm's law). A developmental switch in the molecular machinery controlling concentration of chloride inside the cell – and, hence, the direction of this ion flow – is responsible for the changes in the functional role of GABA between the neonatal and adult stages. That is to say, GABA's role changes from excitatory to inhibitory as the brain develops into adulthood.
While GABA is an inhibitory transmitter in the mature brain, its actions are primarily excitatory in the developing brain. The gradient of chloride is reversed in immature neurons, and its reversal potential is 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, i.e. a depolarizing current. The differential gradient of chloride in immature neurons is primarily due to the higher concentration of NKCC1 co-transporters relative to KCC2 co-transporters in immature cells. GABA itself is partially responsible for orchestrating the maturation of ion pumps. GABA-ergic interneurons mature faster in the hippocampus and the GABA signalling machinery appears earlier than glutamatergic transmission. Thus, GABA is the major excitatory neurotransmitter in many regions of the brain before the maturation of glutamatergic synapses.
However, this theory has been questioned based on results showing that in brain slices of immature mice incubated in artificial cerebrospinal fluid (ACSF) (modified in a way that takes into account the normal composition of the neuronal milieu in sucklings by adding an energy substrate alternative to glucose, beta-hydroxybutyrate) GABA action shifts from excitatory to inhibitory mode.
This effect has been later repeated when other energy substrates, pyruvate and lactate, supplemented glucose in the slices' media. Later investigations of pyruvate and lactate metabolism found that the original results were not due to energy source issues but to changes in pH resulting from the substrates acting as "weak acids". These arguments were later rebutted by further findings showing that changes in pH even greater than that caused by energy substrates do not affect the GABA-shift described in the presence of energy substrate-fortified ACSF and that the mode of action of beta-hydroxybutyrate, pyruvate and lactate (assessed by measurement NAD(P)H and oxygen utilization) was energy metabolism-related.
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. The ganglionic eminences also contribute greatly to building up the GABAergic cortical cell population.
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. GABA activates the GABAA receptor, causing cell cycle arrest in the S-phase, limiting growth.
Beyond the nervous system
GABAergic mechanisms have been demonstrated in various peripheral tissues and organs including, but not restricted to, the intestine, stomach, pancreas, Fallopian tube, uterus, ovary, testis, kidney, urinary bladder, lung, and liver.
In 2007, an excitatory GABAergic system was described in the airway epithelium. The system activates following exposure to allergens and may participate in the mechanisms of asthma. GABAergic systems have also been found in the testis and in the eye lens.
Structure and conformation
GABA is found mostly as a zwitterion, that is, with the carboxy group deprotonated and the amino group protonated. Its conformation depends on its environment. In the gas phase, a highly folded conformation is strongly favored because of the electrostatic attraction between the two functional groups. The stabilization is about 50 kcal/mol, according to quantum chemistry calculations. In the solid state, a more 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.
Gamma-aminobutyric acid was first synthesized in 1883, and was first known only as a plant and microbe metabolic product. In 1950, however, GABA was discovered to be an integral part of the mammalian central nervous system.
Endogenous GABA does not penetrate the blood–brain barrier; it is synthesized in the brain. It is synthesized from glutamate using the enzyme L-glutamic acid decarboxylase (GAD) and pyridoxal phosphate (which is the active form of vitamin B6) as a cofactor. GABA is converted back to glutamate by a metabolic pathway called the GABA shunt. This process converts glutamate, the principal excitatory neurotransmitter, into the principal inhibitory neurotransmitter (GABA).
GABA transaminase enzyme catalyzes 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.
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. Many of the substances below are known to cause anterograde amnesia and retrograde amnesia.
In general, GABA does not cross the blood–brain barrier, 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. At least one study suggests that orally administered GABA increases the amount of Human Growth Hormone (HGH). 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. Certain pro-drugs of GABA (ex. picamilon) have been developed to permeate the blood–brain barrier, then separate into GABA and the carrier molecule once inside the brain. This allows for a direct increase of GABA levels throughout all areas of the brain, in a manner following the distribution pattern of the pro-drug prior to metabolism.
- GABAA receptor ligands
- Agonists/Positive allosteric modulators: ethanol, barbiturates, benzodiazepines, carisoprodol, chloral hydrate, etaqualone, etomidate, glutethimide, kava, methaqualone, muscimol, neuroactive steroids, z-drugs, propofol, skullcap, valerian, theanine, volatile/inhaled anaesthetics.
- Antagonists/Negative allosteric modulators: bicuculline, cicutoxin, flumazenil, furosemide, gabazine, oenanthotoxin, picrotoxin, Ro15-4513, thujone.
- GABAB receptor ligands
- GABA reuptake inhibitors: deramciclane, hyperforin, tiagabine.
- GABA-transaminase inhibitors: gabaculine, phenelzine, valproate, vigabatrin, lemon balm (Melissa officinalis).
- GABA analogues: pregabalin, gabapentin.
- Others: GABA (itself), L-glutamine, picamilon, progabide.
GABA as a supplement
A number of commercial sources sell formulations of GABA for use as a dietary supplement, sometimes for sublingual administration. These sources typically claim that the supplement has a calming effect. These claims are not utterly unreasonable given the nature of GABA in human sympatholysis, but GABA as a tranquilizing agent, purely isolated in itself, is scientifically unsubstantiated or only irregularly demonstrated. For example, there is evidence stating that the calming effects of GABA can be observed in the human brain after administration of GABA as an oral supplement. However, there is also more scientifically and medicinally relevant evidence that pure GABA does not cross the blood–brain barrier at therapeutically significant levels in mice treated with amino oxyacetic acid (GABA transaminase inhibitor). In untreated animals (mice and rabbits) GABA markers (H3) were found distributed over several major unidentified metabolites (except glutamine), which seemed to move into or from brain.
While GABA may not ordinarily cross the blood–brain barrier, it is important to note that studies have shown that, within individuals for whom the blood–brain barrier has been damaged (temporarily for experimental purposes, or as a result of other problems), GABA does indeed have a positive effect, albeit with side effects.The only way to deliver GABA effectively is to circumvent the blood–brain barrier. Indeed, there are a small, limited number of over-the-counter supplements that are derivatives of GABA, such as phenibut and picamilon. Picamilon combines niacin and GABA and crosses the blood–brain barrier as a prodrug that later hydrolyzes into GABA and niacin.
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The role of GABA in the pathogenesis and treatment of anxiety and other neuropsychiatric disorders
- Scholarpedia article on GABA
- List of GABA neurons on NeuroLex.org