Gamma-Aminobutyric acid

γ-Aminobutyric acid (GABA) (, or the acronym ) is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system. In insect species GABA acts only on excitatory nerve receptors. In humans, GABA is, among other things, directly responsible for the regulation of muscle tone.

Although chemically 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, conventionally refers to the alpha amino acids, which GABA is not, nor is it 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. Baclofen, a GABA substitute that can bind to the damaged nerves because of an extra marker added to it that makes it technically (but not really) a different compound, is sometimes used to treat spasticity caused by the non-absorption of regular GABA, and is sometimes, though not always, successful in doing so.

Neurotransmitter
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. Depending on which ion channels open, the membrane potential is either hyperpolarized or depolarized. 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 excitatory 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 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 minimises the effect of any coincident synaptic input essentially by reducing the electrical resistance of the cell's membrane (essentially 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.

Development
In hippocampus and neocortex of the mammalian brain, GABA has primarily excitatory effects early in development, and is in fact the major excitatory neurotransmitter in many regions of the brain before the maturation of glutamate synapses - See developing cortex.

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.

GABA regulates the proliferation of neural progenitor cells the migration and differentiation  the elongation of neurites and the  formation of synapses.

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.

History
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.

Synthesis
Since GABA does not penetrate the blood brain barrier, GABA is therefore synthesized in vivo. It is synthesized from glutamate using the enzyme L-glutamic acid decarboxylase and pyridoxal phosphate (which is the active form of vitamin B6) as a cofactor via a metabolic pathway called the GABA shunt. This process converts glutamate, the principal excitatory neurotransmitter, into the principal inhibitory neurotransmitter (GABA).

Pharmacology
Drugs that act as agonists 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 which have no effective blood brain barrier, such as the periventricular nucleus, can be reached by drugs such as systematically injected GABA. At least one study suggests that orally administered GABA increases the amount of Human Growth Hormone. 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.

GABAergic Drugs

 * GABAA receptor ligands
 * Agonists/Positive allosteric modulators: alcohol,  barbiturates, benzodiazepines, carisoprodol, chloral hydrate, etomidate, glutethimide, L-theanine, kava, methaqualone, muscimol, neuroactive steroids, nonbenzodiazepines, propofol, scullcap, valerian, volatile/inhaled anaesthetics.
 * Antagonists/Negative allosteric modulators: bicuculline, cicutoxin, flumazenil, furosemide, gabazine, oenanthotoxin, picrotoxin, Ro15-4513, thujone.
 * GABAB Receptor Ligands
 * Agonists: baclofen, GBL, GHB, phenibut.
 * Antagonists: phaclofen, saclofen.
 * 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, tetanospasmin.