Gamma-aminobutyric acid
Encyclopedia
γ-Aminobutyric acid is the chief inhibitory neurotransmitter
in the mammal
ian central nervous system
. It plays a role in regulating neuron
al excitability throughout the nervous system
. In humans, GABA is also 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 ever incorporated into a protein
.
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 the brain
by binding to specific transmembrane receptor
s in the plasma membrane of both pre- and postsynaptic neuronal processes. This binding causes the opening of ion channel
s 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 repolarized. 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 receptor
s, which are G protein-coupled receptor
s that open or close ion channels via intermediaries (G protein
s).
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 insect
s, mediating muscle
activation at synapses between nerve
s and muscle cells, and also the stimulation of certain gland
s. In mammals, some GABAergic neurons, such as chandelier cell
s, 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 minimises 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.
and neocortex
of the mammalian brain, GABA has primarily excitatory effects, and is in fact the major excitatory neurotransmitter in many regions of the brain before the maturation
of glutamateergic 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. The effects of beta-hydroxybutyrate were later confirmed for pyruvate and for lactate. However it was argued that the concentrations of the alternative energy substrates used in these experiments were non-physiological and the GABA-shift was instead caused by 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.
GABA regulates the proliferation of neural progenitor cell
s the migration and differentiation
the elongation of neurite
s and the formation of synapses.
GABA also regulates the growth of embryonic
and neural stem cell
s. 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.
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.
, 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.
.
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).
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.
s (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 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.
, sometimes for sublingual administration. These sources typically make claims that the supplement has a calming effect. No scientific assessment of such claims exists, but because of the extensive evidence that GABA does not cross the blood-brain barrier
at significant levels, their validity is doubtful. However some over-the-counter supplements such as Picamilon
can cross the barrier due to added macro-molecules that later hydrolyze into its constituents: GABA and niacin in the case of Picamilon.
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
in the mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
ian central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. It plays a role in regulating neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
al excitability throughout the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
. In humans, GABA is also directly responsible for the regulation of muscle tone
Muscle tone
In physiology, medicine, and anatomy, muscle tone is the continuous and passive partial contraction of the muscles, or the muscle’s resistance to passive stretch during resting state. It helps maintain posture, and it declines during REM sleep.-Purpose:Unconscious nerve impulses maintain the...
.
Although chemically it is an amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
, 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
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
, which GABA is not, nor is it ever incorporated into a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
.
In spastic diplegia
Spastic diplegia
Spastic diplegia, historically known as Little's Disease, is a form of cerebral palsy that is a neuromuscular condition of hypertonia and spasticity in the muscles of the lower extremities of the human body, usually those of the legs, hips and pelvis...
in humans, GABA absorption becomes impaired by nerves damaged from the condition's upper motor neuron
Upper motor neuron
Upper motor neurons are motor neurons that originate in the motor region of the cerebral cortex or the brain stem and carry motor information down to the final common pathway, that is, any motor neurons that are not directly responsible for stimulating the target muscle...
lesion, which leads to hypertonia
Hypertonia
Hypertonia a condition marked by an abnormal increase in muscle tension and a reduced ability of a muscle to stretch. It is caused by lesions to upper motor neurons in the central nervous system, which carry information from the central nervous system to the muscles and control posture, muscle...
of the muscles signaled by those nerves that can no longer absorb GABA.
Neurotransmitter
In vertebrates, GABA acts at inhibitory synapsesChemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...
in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
by binding to specific transmembrane receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s in the plasma membrane of both pre- and postsynaptic neuronal processes. This binding causes the opening of ion channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s to allow the flow of either negatively charged chloride
Chloride
The chloride ion is formed when the element chlorine, a halogen, picks up one electron to form an anion Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. The chloride ion, and its salts such as sodium chloride, are very soluble in water...
ions into the cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
or positively charged potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
ions out of the cell. Depending on which ion channels open, the membrane potential is either hyperpolarized or repolarized. This action results in a negative change in the transmembrane potential, usually causing hyperpolarization
Hyperpolarization (biology)
Hyperpolarization is a change in a cell's membrane potential that makes it more negative. It is the opposite of a depolarization.Hyperpolarization is often caused by efflux of K+ through K+ channels, or influx of Cl– through Cl– channels. On the other hand, influx of cations, e.g...
. Two general classes of GABA receptor
GABA receptor
The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid , the chief inhibitory neurotransmitter in the vertebrate central nervous system...
are known: GABAA in which the receptor is part of a ligand-gated ion channel
Ligand-gated ion channel
Ligand-gated ion channels are one type of ionotropic receptor or channel-linked receptor. They are a group of transmembrane ion channels that are opened or closed in response to the binding of a chemical messenger , such as a neurotransmitter.The binding site of endogenous ligands on LGICs...
complex, and GABAB metabotropic receptor
Metabotropic receptor
Metabotropic receptor is a subtype of membrane receptors at the surface or in vesicles of eukaryotic cells.In the nervous system, based on their structural and functional characteristics, neurotransmitter receptors can be classified into two broad categories: metabotropic and ionotropic receptors...
s, which are G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
s that open or close ion channels via intermediaries (G protein
G protein
G proteins are a family of proteins involved in transmitting chemical signals outside the cell, and causing changes inside the cell. They communicate signals from many hormones, neurotransmitters, and other signaling factors. G protein-coupled receptors are transmembrane receptors...
s).
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
Medium spiny neuron
The medium spiny neurons are a special type of inhibitory cells representing approximately 90% of the neurons within the corpus striatum of the basal ganglia. They play a key role in initiating and controlling movements of the body, limbs, and eyes....
are a typical example of inhibitory CNS
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
GABAergic cells. In contrast, GABA exhibits both excitatory and inhibitory actions in insect
Insect
Insects are a class of living creatures within the arthropods that have a chitinous exoskeleton, a three-part body , three pairs of jointed legs, compound eyes, and two antennae...
s, mediating muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
activation at synapses between nerve
Nerve
A peripheral nerve, or simply nerve, is an enclosed, cable-like bundle of peripheral axons . A nerve provides a common pathway for the electrochemical nerve impulses that are transmitted along each of the axons. Nerves are found only in the peripheral nervous system...
s and muscle cells, and also the stimulation of certain gland
Gland
A gland is an organ in an animal's body that synthesizes a substance for release of substances such as hormones or breast milk, often into the bloodstream or into cavities inside the body or its outer surface .- Types :...
s. In mammals, some GABAergic neurons, such as chandelier cell
Chandelier cell
Chandelier neurons or chandelier cells are a subset of GABA-ergic cortical interneurons. They are described as parvalbumin-containing and fast-spiking to distinguish them from other subtypes of GABAergic neurons. The name comes from the specific shape of their axon arbors, with the terminals...
s, 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
Chloride
The chloride ion is formed when the element chlorine, a halogen, picks up one electron to form an anion Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. The chloride ion, and its salts such as sodium chloride, are very soluble in water...
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
Shunting inhibition
Shunting inhibition is termed "shunting" because the synaptic conductance short-circuits currents that are generated at adjacent excitatory synapses. If a shunting inhibitory synapse is activated, the input resistance is reduced locally and, following Ohm's law, the amplitude of subsequent...
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 (in essence, equivalent to Ohm's law
Ohm's law
Ohm's law states that the current through a conductor between two points is directly proportional to the potential difference across the two points...
). 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.
Brain development
For the past two decades, the theory of excitatory action of GABA early in development was unquestioned based on experiments in vitro, on brain slices. The main observation was that in the hippocampusHippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
and neocortex
Neocortex
The neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...
of the mammalian brain, GABA has primarily excitatory effects, and is in fact the major excitatory neurotransmitter in many regions of the brain before the maturation
Neural development
Neural development comprises the processes that generate, shape, and reshape the nervous system, from the earliest stages of embryogenesis to the final years of life. The study of neural development aims to describe the cellular basis of brain development and to address the underlying mechanisms...
of glutamateergic 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
Pyruvic acid
Pyruvic acid is an organic acid, a ketone, as well as the simplest of the alpha-keto acids. The carboxylate ion of pyruvic acid, CH3COCOO−, is known as pyruvate, and is a key intersection in several metabolic pathways....
and lactate
Lactic acid
Lactic acid, also known as milk acid, is a chemical compound that plays a role in various biochemical processes and was first isolated in 1780 by the Swedish chemist Carl Wilhelm Scheele. Lactic acid is a carboxylic acid with the chemical formula C3H6O3...
, supplemented glucose in the slices' media. The effects of beta-hydroxybutyrate were later confirmed for pyruvate and for lactate. However it was argued that the concentrations of the alternative energy substrates used in these experiments were non-physiological and the GABA-shift was instead caused by 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.
GABA regulates the proliferation of neural progenitor cell
Progenitor cell
A progenitor cell is a biological cell that, like a stem cell, has a tendency to differentiate into a specific type of cell, but is already more specific than a stem cell and is pushed to differentiate into its "target" cell...
s the migration and differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
the elongation of neurite
Neurite
A neurite refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture, because it can be difficult to tell axons from dendrites before...
s and the formation of synapses.
GABA also regulates the growth of embryonic
Embryonic stem cell
Embryonic stem cells are pluripotent stem cells derived from the inner cell mass of the blastocyst, an early-stage embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consist of 50–150 cells...
and neural stem cell
Neural stem cell
Neural stem cells are the self-renewing, multipotent cells that generate the main phenotypes of the nervous system. In 1989, Sally Temple described multipotent, self-renewing progenitor and stem cells in the subventricular zone of the mouse brain . In 1992, Brent A...
s. GABA can influence the development of neural progenitor cells via brain-derived neurotrophic factor
Brain-derived neurotrophic factor
Brain-derived neurotrophic factor, also known as BDNF, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the "neurotrophin" family of growth factors, which are related to the canonical "Nerve Growth Factor", NGF...
(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
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
. The system activates following exposure to allergens and may participate in the mechanisms of asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
. GABAergic systems have also been found in the testis and in the eye lens.
Structure and conformation
GABA is found mostly as a zwitterionZwitterion
In chemistry, a zwitterion is a neutral molecule with a positive and a negative electrical charge at different locations within that molecule. Zwitterions are sometimes also called inner salts.-Examples:...
, that is, with the carboxy group deprotonated and the amino group protonated. Its conformation
Conformational isomerism
In chemistry, conformational isomerism is a form of stereoisomerism in which the isomers can be interconverted exclusively by rotations about formally single bonds...
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
Quantum chemistry
Quantum chemistry is a branch of chemistry whose primary focus is the application of quantum mechanics in physical models and experiments of chemical systems...
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
Solvation
Solvation, also sometimes called dissolution, is the process of attraction and association of molecules of a solvent with molecules or ions of a solute...
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 systemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
.
Synthesis
GABA does not penetrate the blood-brain barrier; it is synthesized in the brain. It is synthesized from glutamate using the enzymeEnzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
L-glutamic acid decarboxylase and pyridoxal phosphate (which is the active form of vitamin B6) as a cofactor
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
via a metabolic pathway called the GABA shunt. This process converts glutamate, the principal excitatory neurotransmitter, into the principal inhibitory neurotransmitter (GABA).
Catabolism
GABA transaminase enzyme catalyzes the conversion of 4-aminobutanoic acid and 2-oxoglutarate into succinic semialdehydeSuccinic semialdehyde
Succinic semialdehyde is a GABA analogue.-See also:* Succinic semialdehyde dehydrogenase deficiency* 4-aminobutyrate aminotransferase...
and glutamate. Succinic semialdehyde is then oxidized into succinic acid
Succinic acid
Succinic acid is a dicarboxylic acid. Succinate plays a biochemical role in the citric acid cycle. The name derives from Latin succinum, meaning amber, from which the acid may be obtained....
by succinic semialdehyde dehydrogenase and as such enters the citric acid cycle
Citric acid cycle
The citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...
as a usable source of energy.
Pharmacology
Drugs that act as allosteric modulators of GABA receptorGABA receptor
The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid , the chief inhibitory neurotransmitter in the vertebrate central nervous system...
s (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
Anterograde amnesia
Anterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...
and retrograde amnesia
Retrograde amnesia
Retrograde amnesia is a loss of access to events that occurred, or information that was learned, before an injury or the onset of a disease....
.
In general, GABA does not cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
, although certain areas of the brain that have no effective blood-brain barrier, such as the periventricular nucleus
Periventricular nucleus
The Periventricular nucleus is a thin sheet of small neurons located in the wall of the third ventricle, a composite structure of the hypothalamus. Functions in analgesia....
, 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: alcoholEthanolEthanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
, barbiturateBarbiturateBarbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, as hypnotics, and as anticonvulsants...
s, benzodiazepineBenzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s, carisoprodolCarisoprodolCarisoprodol is a centrally-acting skeletal muscle relaxant. Carisoprodol is slightly soluble in water and freely soluble in alcohol, chloroform and acetone. The drug's solubility is practically independent of pH. Carisoprodol is manufactured and marketed in the United States by Meda Pharmaceuticals...
, chloral hydrateChloral hydrateChloral hydrate is a sedative and hypnotic drug as well as a chemical reagent and precursor. The name chloral hydrate indicates that it is formed from chloral by the addition of one molecule of water. Its chemical formula is C2H3Cl3O2....
, etomidateEtomidateEtomidate is a short acting intravenous anaesthetic agent used for the induction of general anaesthesia and for sedation for short procedures such as reduction of dislocated joints, tracheal intubation and cardioversion...
, glutethimideGlutethimideGlutethimide is a hypnotic sedative that was introduced in 1954 as a safe alternative to barbiturates to treat insomnia. Before long, however, it had become clear that glutethimide was just as likely to cause addiction and caused similarly severe withdrawal symptoms...
, L-theanine, kavaKavaKava or kava-kava is a crop of the western Pacific....
, methaqualoneMethaqualoneMethaqualone is a sedative-hypnotic drug that is similar in effect to barbiturates, a general central nervous system depressant. The sedative-hypnotic activity was first noted by Indian researchers in the 1950s and in 1962 methaqualone itself was patented in the US by Wallace and Tiernan...
, muscimolMuscimolMuscimol is the major psychoactive alkaloid present in many mushrooms of the Amanita genus. Unlike psilocin , which is a serotonergic psychedelic and agonist for the 5-HT2A receptor set, muscimol is a potent, selective agonist for the GABAA receptor set and is a deliriant as a opposed...
, neuroactive steroidNeuroactive steroidNeuroactive steroids rapidly alter neuronal excitability through interaction with neurotransmitter-gated ion channels. In addition, these steroids may also exert effects on gene expression via intracellular steroid hormone receptors...
s, z-drugZ-drugZ-drugs are a group of nonbenzodiazepine drugs with effects similar to benzodiazepines which are used in the treatment of insomnia, and whose names mostly start with the letter "Z". Some Z drugs may have advantages over benzodiazepines...
s, propofolPropofolPropofol is a short-acting, intravenously administered hypnotic agent. Its uses include the induction and maintenance of general anesthesia, sedation for mechanically ventilated adults, and procedural sedation. Propofol is also commonly used in veterinary medicine...
, scullcapScutellaria laterifloraScutellaria lateriflora, also known as Blue Skullcap, Hoodwort, Virginian Skullcap, Mad-dog Skullcap is a hardy perennial herb native to North America. It is a member of the mint family. It has an upright habit, growing 60 to 80 centimeters in maximum height. It is a wetland-loving species and...
, valerianValerian (herb)Valerian is a hardy perennial flowering plant, with heads of sweetly scented pink or white flowers which bloom in the summer months. Valerian flower extracts were used as a perfume in the sixteenth century....
, volatile/inhaled anaestheticInhalational anaestheticAn inhalational anaesthetic is a chemical compound possessing general anaesthetic properties that can be delivered via inhalation. They are administered by anaesthetists through an anaesthesia mask, laryngeal mask airway or tracheal tube connected to some type of anaesthetic vaporiser and an...
s. - Antagonists/Negative allosteric modulators: bicucullineBicucullineBicuculline is a light-sensitive competitive antagonist of GABAA receptors. It was originally identified in 1932 in plant alkaloid extracts and has been isolated from Dicentra cucullaria, Adlumia fungosa, Fumariaceae, and several Corydalis species. Since it blocks the inhibitory action of GABA...
, cicutoxinCicutoxinCicutoxin is a poisonous polyyne and alcohol found in various plants, most notably water hemlock . It is structurally related to the oenanthotoxin of hemlock water dropwort....
, flumazenilFlumazenilFlumazenil is a benzodiazepine antagonist available for injection only, and the only benzodiazepine receptor antagonist on the market today.It was first introduced in 1987 by Hoffmann-La Roche under the trade name Anexate, but only approved by...
, furosemideFurosemideFurosemide or frusemide is a loop diuretic used in the treatment of congestive heart failure and edema. It is most commonly marketed by Sanofi-Aventis under the brand name Lasix...
, gabazineGabazineGabazine is a drug that acts as an antagonist at GABAA receptors. It is used in scientific research and has no role in medicine, as it would be expected to produce convulsions if used in humans....
, oenanthotoxinOenanthotoxinOenanthotoxin is a toxin extracted from hemlock water dropwort and other plants of the genus Oenanthe. It is a central nervous system poison, and acts as a noncompetitive gamma-aminobutyric acid antagonist. This toxin played some role in euthanasia in ancient Sardinia, for inducing risus...
, picrotoxinPicrotoxinPicrotoxin, also known as cocculin, is a poisonous crystalline plant compound, first isolated by Pierre Boullay in 1812. The name "picrotoxin" is a combination of the Greek words "picros" and "toxicon" ....
, Ro15-4513Ro15-4513Ro15-4513 is a weak partial inverse agonist of the benzodiazepine class of drugs, developed by Hoffmann–La Roche in 1984, and is structurally related to the benzodiazepine antidote flumazenil.-Original development as alcohol antidote:...
, thujoneThujoneThujone is a ketone and a monoterpene that occurs naturally in two diastereomeric forms: -α-thujone and -β-thujone. It has a menthol odor. Even though it is best known as a chemical compound in the spirit absinthe, recent tests show absinthe contains only small quantities of thujone, and may or may...
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- Agonists/Positive allosteric modulators: alcohol
- GABAB Receptor Ligands
- Agonists: baclofenBaclofenBaclofen is a derivative of gamma-aminobutyric acid . It is primarily used to treat spasticity and is under investigation for the treatment of alcoholism....
, GBLGamma-Butyrolactonegamma-Butyrolactone is a hygroscopic colorless oily liquid with a weak characteristic odor and is soluble in water. GBL is a common solvent and reagent in chemistry and is used as an aroma compound, as a stain remover, as a superglue remover, as a paint stripper, and as a solvent in some wet...
, GHBGamma-Hydroxybutyric acidγ-Hydroxybutyric acid , also known as 4-hydroxybutanoic acid and sodium oxybate when used for medicinal purposes, is a naturally occurring substance found in the central nervous system, wine, beef, small citrus fruits, and almost all animals in small amounts. It is also categorized as an illegal...
, phenibutPhenibutβ-Phenyl-γ-aminobutyric acid, better known as phenibut or less commonly fenibut or phenybut, is a derivative of the naturally occurring inhibitory neurotransmitter γ-aminobutyric acid . The addition of a phenyl ring allows phenibut to cross the blood brain barrier...
. - Antagonists: phaclofenPhaclofenPhaclofen, or phosphonobaclofen, is a selective antagonist for the GABAB receptor....
, saclofenSaclofenSaclofen is a competitive antagonist for the GABAB receptor. This drug is an analogue of the GABAB agonist Baclofen. The GABAB receptor is heptahelical receptor, expressed as an obligate heterodimer, which couples to the Gi/o class of heterotrimeric G-proteins...
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- Agonists: baclofen
- GABA reuptake inhibitorGABA reuptake inhibitorA GABA reuptake inhibitor is a type of drug which acts as a reuptake inhibitor for the neurotransmitter gamma-Aminobutyric acid by blocking the action of the gamma-Aminobutyric acid transporters...
s: deramciclaneDeramciclaneDeramciclane is a drug which acts as an antagonist at the 5-HT2A receptor, as an inverse agonist at the 5-HT2C receptor, and as a GABA reuptake inhibitor....
, hyperforinHyperforinHyperforin is a phytochemical produced by some of the members of the plant genus Hypericum, notably Hypericum perforatum .- Occurrence :...
, tiagabineTiagabineTiagabine -Indications:Tiagabine is approved by U.S. Food and Drug Administration as an adjunctive treatment for partial seizures in ages 12 and up. It may also be prescribed to treat anxiety disorders and neuropathic pain . For anxiety and neuropathic pain, tiagabine is used primarily to augment...
. - GABA-transaminase inhibitors: gabaculineGabaculineGabaculine is a naturally occurring neurotoxin first isolated from the bacteria Streptomyces toyacaensis, which acts as a potent and irreversible GABA transaminase inhibitor, and also a GABA reuptake inhibitor....
, phenelzinePhenelzinePhenelzine is a non-selective and irreversible monoamine oxidase inhibitor of the hydrazine class which is used as an antidepressant and anxiolytic...
, valproate, vigabatrinVigabatrinVigabatrin is an antiepileptic drug that inhibits the catabolism of gamma-aminobutyric acid by irreversibly inhibiting GABA transaminase. It is an analog of GABA, but it is not a receptor agonist...
, Lemon balmLemon balmLemon balm , not to be confused with bee balm, Monarda species, is a perennial herb in the mint family Lamiaceae, native to southern Europe and the Mediterranean region....
(Melissa officinalis). - GABA analogues: pregabalinPregabalinPregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. It has also been found effective for generalized anxiety disorder and is approved for this use in the European Union. It was designed...
, gabapentinGabapentinGabapentin is a pharmaceutical drug, specifically a GABA analogue. It was originally developed for the treatment of epilepsy, and currently is also used to relieve neuropathic pain...
. - Others: GABA (itself), L-glutamine, picamilonPicamilonPicamilon is a dietary supplement formed by combining niacin with GABA. It was developed in the Soviet Union in 1969 by the All-Union Vitamins Scientific Research Institute and further studied in both Russia and Japan as a prodrug of GABA.Picamilon is sold in the United States as a dietary...
, progabideProgabideProgabide is an analog and prodrug of gamma-aminobutyric acid used in the treatment of epilepsy...
, tetanospasminTetanospasminTetanus toxin is an extremely potent neurotoxin produced by the vegetative cell of Clostridium tetani in anaerobic conditions, causing tetanus. It has no known function for clostridia in the soil environment where they are normally encountered. It is also called spasmogenic toxin, tetanospasmin or...
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GABA as a supplement
A number of commercial sources sell formulations of GABA for use as a dietary supplementDietary supplement
A dietary supplement, also known as food supplement or nutritional supplement, is a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantities in a person's diet...
, sometimes for sublingual administration. These sources typically make claims that the supplement has a calming effect. No scientific assessment of such claims exists, but because of the extensive evidence that GABA does not cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
at significant levels, their validity is doubtful. However some over-the-counter supplements such as Picamilon
Picamilon
Picamilon is a dietary supplement formed by combining niacin with GABA. It was developed in the Soviet Union in 1969 by the All-Union Vitamins Scientific Research Institute and further studied in both Russia and Japan as a prodrug of GABA.Picamilon is sold in the United States as a dietary...
can cross the barrier due to added macro-molecules that later hydrolyze into its constituents: GABA and niacin in the case of Picamilon.
See also
- Germinated brown rice
- SpasticitySpasticitySpasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...
- Spastic diplegiaSpastic diplegiaSpastic diplegia, historically known as Little's Disease, is a form of cerebral palsy that is a neuromuscular condition of hypertonia and spasticity in the muscles of the lower extremities of the human body, usually those of the legs, hips and pelvis...
, a GABA deficiency neuromuscular neuropathologyNeuropathologyNeuropathology is the study of disease of nervous system tissue, usually in the form of either small surgical biopsies or whole autopsy brains. Neuropathology is a subspecialty of anatomic pathology, neurology, and neurosurgery...