GABA A receptor
Encyclopedia
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...
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...
. Its endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter
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 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...
. Upon activation, the GABAA receptor selectively conducts Cl-
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...
through its pore
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...
, resulting in 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...
of the 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...
. This causes an inhibitory effect on neurotransmission
Neurotransmission
Neurotransmission , also called synaptic transmission, is the process by which signaling molecules called neurotransmitters are released by a neuron , and bind to and activate the receptors of another neuron...
by diminishing the chance of a successful action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
occurring.
The active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
of the GABAA receptor is the binding site for GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
and several drugs such as muscimol
Muscimol
Muscimol 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...
, gaboxadol
Gaboxadol
Gaboxadol also known as 4,5,6,7-tetrahydroisoxazolopyridin-3-ol is an experimental sleep aid drug developed by Lundbeck and Merck. In March, 2007, Merck and H. Lundbeck cancelled work on the drug, citing safety concerns and the failure of an efficacy trial...
, and bicuculline
Bicuculline
Bicuculline 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...
. The protein also contains a number of different allosteric binding sites which modulate the activity of the receptor indirectly. These allosteric sites are the targets of various other drugs, including the benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s, nonbenzodiazepine
Nonbenzodiazepine
The nonbenzodiazepines, also called benzodiazepine-like drugs, are a class of psychoactive drugs pharmacologically resembling the benzodiazepines, with similar benefits, side effects and risks, despite having dissimilar or entirely different chemical structures.-Classes:There are currently three...
s, barbiturate
Barbiturate
Barbiturates 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, ethanol
Ethanol
Ethanol, 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...
, neuroactive steroid
Neuroactive steroid
Neuroactive 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, inhaled anaesthetics
Inhalational anaesthetic
An 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...
, and picrotoxin
Picrotoxin
Picrotoxin, 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" ....
, among others.
Mild inhibition of neuronal firing by drugs acting at the GABAA receptor causes a reduction of anxiety in the patient (an anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
effect) while more pronounced inhibition induces sleep (sedation
Sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
) and in extreme cases of overdose, may result in death.
Target for benzodiazepines
The ionotropic GABAA receptor protein complex is also the molecular target of the benzodiazepineBenzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
(BZ) class of tranquilizer drugs. Benzodiazepines do not bind to the same receptor site on the protein complex as the endogenous ligand GABA
Gamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
(whose binding site is located between α- and β-subunits), but bind to distinct benzodiazepine binding sites situated at the interface between the α- and γ-subunits of α- and γ-subunit containing GABAA receptors (see figure to the right). While the majority of GABAA receptors (those containing α1-, α2-, α3-, or α5-subunits) are benzodiazepine sensitive there exists a minority of GABAA receptors (α4- or α6-subunit containing) which are insensitive to classical 1,4-benzodiazepines, but instead are sensitive to other classes of GABAergic drugs such as the neurosteroids and alcohol
Alcoholic beverage
An alcoholic beverage is a drink containing ethanol, commonly known as alcohol. Alcoholic beverages are divided into three general classes: beers, wines, and spirits. They are legally consumed in most countries, and over 100 countries have laws regulating their production, sale, and consumption...
. In addition peripheral benzodiazepine receptors exist which are not associated with GABAA receptors. As a result the IUPHAR
International Union of Basic and Clinical Pharmacology
The International Union of Basic and Clinical Pharmacology is a voluntary, non-profit association representing the interests of scientists in pharmacology-related fields to facilitate Better Medicines through Global Education and Research around the world.-History:Established in 1959 as a section...
has recommended that the terms "BZ receptor", "GABA/BZ receptor" and "omega receptor" no longer be used and that the term "benzodiazepine receptor" be replaced with "benzodiazepine site".
In order for GABAA receptors to be sensitive to the action of benzodiazepines they need to contain an α and a γ subunit, where the benzodiazepine binds. Once bound, the benzodiazepine locks the GABAA receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABAA receptor, increasing the frequency of opening of the associated chloride ion channel and hyperpolarising the membrane. This potentiates the inhibitory effect of the available GABA leading to sedatory and anxiolytic effects.
Different benzodiazepines have different affinities for GABAA receptors made up of different collection of subunits, and this means that their pharmacological profile varies with subtype selectivity. For instance, benzodiazepine receptor ligands with high activity at the α1 and/or α5 tend to be more associated with sedation
Sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
, ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
and amnesia
Amnesia
Amnesia is a condition in which one's memory is lost. The causes of amnesia have traditionally been divided into categories. Memory appears to be stored in several parts of the limbic system of the brain, and any condition that interferes with the function of this system can cause amnesia...
, whereas those with higher activity at GABAA receptors containing α2 and/or α3 subunits generally have greater anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
activity. Anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
effects can be produced by agonists acting at any of the GABAA subtypes, but current research in this area is focused mainly on producing α2-selective agonists as anticonvulsants which lack the side effects of older drugs such as sedation and amnesia.
The binding site for benzodiazepines is distinct from the binding site for barbiturates and GABA on the GABAA receptor, and also produces different effects on binding, with the benzodiazepines causing bursts of chloride channel opening to occur more often, while the barbiturates cause the duration of bursts of chloride channel opening to become longer. Since these are separate modulatory effects, they can both take place at the same time, and so the combination of benzodiazepines with barbiturates is strongly synergistic, and can be dangerous if dosage is not strictly controlled.
Also note that some GABAA agonists such as muscimol
Muscimol
Muscimol 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...
and gaboxadol
Gaboxadol
Gaboxadol also known as 4,5,6,7-tetrahydroisoxazolopyridin-3-ol is an experimental sleep aid drug developed by Lundbeck and Merck. In March, 2007, Merck and H. Lundbeck cancelled work on the drug, citing safety concerns and the failure of an efficacy trial...
do bind to the same site on the GABAA receptor complex as GABA itself, and consequently produce effects which are similar but not identical to those of positive allosteric modulators like benzodiazepines.
Structure and function
Oligomer
In chemistry, an oligomer is a molecule that consists of a few monomer units , in contrast to a polymer that, at least in principle, consists of an unlimited number of monomers. Dimers, trimers, and tetramers are oligomers. Many oils are oligomeric, such as liquid paraffin...
transmembrane receptor that consists of five subunits arranged around a central pore. The receptor sits in the membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
of its 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...
, usually localized at a synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
, postsynaptically. However, some isoforms may be found extrasynaptically. The ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
GABA is the endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
compound that causes this receptor to open; once bound to GABA, the 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...
receptor changes conformation within the membrane, opening the pore in order to allow 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...
anions (Cl−) to pass down an electrochemical gradient
Membrane potential
Membrane potential is the difference in electrical potential between the interior and exterior of a biological cell. All animal cells are surrounded by a plasma membrane composed of a lipid bilayer with a variety of types of proteins embedded in it...
. Because the reversal potential
Reversal potential
In a biological membrane, the reversal potential of an ion is the membrane potential at which there is no net flow of that particular ion from one side of the membrane to the other...
for chloride in most neurons is close to or more negative than the resting membrane potential
Membrane potential
Membrane potential is the difference in electrical potential between the interior and exterior of a biological cell. All animal cells are surrounded by a plasma membrane composed of a lipid bilayer with a variety of types of proteins embedded in it...
, activation of GABAA receptors tends to stabilize or hyperpolarise the resting potential, and can make it more difficult for excitatory neurotransmitter
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...
s to depolarize
Depolarization
In biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...
the neuron and generate an action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
. The net effect is typically inhibitory, reducing the activity of the neuron. The GABAA channel opens quickly and thus contributes to the early part of the inhibitory post-synaptic potential (IPSP).
The endogenous ligand that binds to the benzodiazepine site is inosine
Inosine
Inosine is a nucleoside that is formed when hypoxanthine is attached to a ribose ring via a β-N9-glycosidic bond....
.
Subunits
GABAA receptors are members of the large "Cys-loop" super-family of evolutionarily related and structurally similar ligand-gated ion channelLigand-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...
s that also includes nicotinic acetylcholine receptor
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
s, glycine receptor
Glycine receptor
The glycine receptor, or GlyR, is the receptor for the amino acid neurotransmitter glycine. GlyR is an ionotropic receptor that produces its effects through chloride current...
s, and the 5HT3 receptor
5-HT3 receptor
The 5-HT3 receptor is a member of the superfamily of ligand-gated ion channels, a superfamily that also includes the neuronal nicotinic acetylcholine receptors , and the inhibitory neurotransmitter receptors for GABA and glycine...
. There are numerous subunit isoforms for the GABAA receptor, which determine the receptor's agonist affinity, chance of opening, conductance, and other properties.
In humans, the units are as follows:
- six types of α subunits (GABRA1GABRA1Gamma-aminobutyric acid receptor subunit alpha-1 is a protein that in humans is encoded by the GABRA1 gene.-Further reading:...
, GABRA2GABRA2Gamma-aminobutyric acid receptor subunit alpha-2 is a protein that in humans is encoded by the GABRA2 gene....
, GABRA3GABRA3Gamma-aminobutyric acid receptor subunit alpha-3 is a protein that in humans is encoded by the GABRA3 gene.- Function :GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABAA receptors, which are ligand-gated chloride channels...
, GABRA4GABRA4Gamma-aminobutyric acid receptor subunit alpha-4 is a protein that in humans is encoded by the GABRA4 gene....
, GABRA5GABRA5Gamma-aminobutyric acid A receptor, alpha 5, also known as GABRA5, is a protein which in humans is encoded by the GABRA5 gene.-Function:...
, GABRA6GABRA6Gamma-aminobutyric acid receptor subunit alpha-6 is a protein that in humans is encoded by the GABRA6 gene.One study has found a genetic variant in the gene to be associated with the personality trait neuroticism....
) - three β's (GABRB1GABRB1Gamma-aminobutyric acid receptor subunit beta-1 is a protein that in humans is encoded by the GABRB1 gene....
, GABRB2GABRB2Gamma-aminobutyric acid receptor subunit beta-2 is a protein that in humans is encoded by the GABRB2 gene....
, GABRB3GABRB3Gamma-aminobutyric acid receptor subunit beta-3 is a protein that in humans is encoded by the GABRB3 gene....
) - three γ's (GABRG1GABRG1Gamma-aminobutyric acid receptor subunit gamma-1 is a protein that in humans is encoded by the GABRG1 gene. The protein encoded by this gene is a subunit of the GABAA receptor.Variants of this gene may be associated with alcohol dependence....
, GABRG2GABRG2Gamma-aminobutyric acid receptor subunit gamma-2 is a protein that in humans is encoded by the GABRG2 gene.-Interactions:GABRG2 has been shown to interact with GABARAP and Dopamine receptor D5.-Further reading:...
, GABRG3GABRG3GABAA receptor-γ3, also known as GABRG3, is a protein which in humans is encoded by the GABRG3 gene.- Function :GABRG3 is a subunit of the GABAA receptor for the neurotransmitter gamma-Aminobutyric acid .- Association with alcoholism :...
) - as well as a δ (GABRDGABRDGamma-aminobutyric acid receptor subunit delta is a protein that in humans is encoded by the GABRD gene....
), an ε (GABREGABREGamma-aminobutyric acid receptor subunit epsilon is a protein that in humans is encoded by the GABRE gene....
), a π (GABRPGABRPGamma-aminobutyric acid receptor subunit pi is a protein that in humans is encoded by the GABRP gene....
), and a θ (GABRQGABRQGamma-aminobutyric acid receptor subunit theta is a protein that in humans is encoded by theGABRQ gene. The protein encoded by this gene is a subunit of the GABAA receptor....
)
There are three ρ units (GABRR1
GABRR1
Gamma-aminobutyric acid receptor subunit rho-1 is a protein that in humans is encoded by the GABRR1 gene.- External links :...
, GABRR2
GABRR2
Gamma-aminobutyric acid receptor subunit rho-2 is a protein that in humans is encoded by the GABRR2 gene.- External links :...
, GABRR3
GABRR3
Gamma-aminobutyric acid receptor subunit rho-3 is a protein that in humans is encoded by the GABRR3 gene. The protein encoded by this gene is a subunit of the GABAA-ρ receptor....
), however these do not coassemble with the classical GABAA units listed above, but rather homooligomerize to form GABAA-ρ receptors (formerly designated as GABAC receptors).
Five subunits can combine in different ways to form GABAA channels. The minimal requirement to produce a GABA-gated ion channel is the inclusion of both α and β subunits, but the most common type in the brain is a pentamer comprising two α's, two β's, and a γ (α2β2γ).
The receptor binds two GABA molecules, at the interface between an α and a β subunit.
Ligands
A number of ligandLigand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
s have been found to bind to various sites on the GABAA receptor complex and modulate it besides GABA itself.
Types
- AgonistAgonistAn agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
s: Bind to the main receptor site (the site where GABA normally binds, also referred to as the "active" or "orthosteric" site) and activate it, resulting in increased Cl- conductance. - AntagonistReceptor antagonistA receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
s: Bind to the main receptor site but do not activate it. Though they have no effect on their own, antagonists compete with GABA for binding and thereby inhibit its action, resulting in decreased Cl- conductance. - Positive Allosteric ModulatorPositive allosteric modulatorA positive allosteric modulator is a drug which increases the activity of a receptor indirectly via activation of an allosteric site on the protein. PAMs are similar to agonists in that they contribute to overall receptor activation, but they are different because they do so in a functionally...
s: Bind to allosteric sites on the receptor complex and affect it in a positive manner, causing increased efficiency of the main site and therefore an indirect increase in Cl- conductance. - Negative Allosteric ModulatorNegative allosteric modulatorA negative allosteric modulator is a drug which decreases the activity of a receptor indirectly via disactivation of an allosteric site on the protein. NAMs are similar to inverse agonists in that they conteract overall receptor activation, but they are different because they do so in a...
s: Bind to an allosteric site on the receptor complex and affect it in a negative manner, causing decreased efficiency of the main site and therefore an indirect decrease in Cl- conductance. - Uncompetitive Channel BlockerChannel blockerA channel blocker or ion channel blocker is a type of drug which binds inside the pore of a specific type of ion channel and blocks the flow of ions through it, resulting in an alteration of the electrochemical gradient of the cell membrane of neurons and therefore a change in...
s: Bind to or near the central pore of the receptor complex and directly block Cl- conductance through the ion channel.
Examples
- Agonists: GABAGabâGabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
, GaboxadolGaboxadolGaboxadol also known as 4,5,6,7-tetrahydroisoxazolopyridin-3-ol is an experimental sleep aid drug developed by Lundbeck and Merck. In March, 2007, Merck and H. Lundbeck cancelled work on the drug, citing safety concerns and the failure of an efficacy trial...
, Ibotenic AcidIbotenic acidIbotenic acid is a chemical compound that is naturally occurring in the mushrooms Amanita muscaria and Amanita pantherina, among others...
, 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...
, ProgabideProgabideProgabide is an analog and prodrug of gamma-aminobutyric acid used in the treatment of epilepsy...
. - Antagonists: 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...
. - Positive Allosteric Modulators: 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...
, EthanolEthanolEthanol, 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...
(Alcohol), 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...
, KavalactoneKavalactoneKavalactones are a class of lactone compounds found in the kava shrub.-Compounds:At least 18 different kavalactones have been identified to date, with methysticin being the first identified.Analogues, such as ethysticin, have also been isolated....
s, MeprobamateMeprobamateMeprobamate is a carbamate derivative which is used as an anxiolytic drug...
, 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...
, 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, NiacinNiacin"Niacin" redirects here. For the neo-fusion band, see Niacin .Niacin is an organic compound with the formula and, depending on the definition used, one of the forty to eighty essential human nutrients.Niacin is one of five vitamins associated with a pandemic deficiency disease: niacin deficiency...
/Niacinamide, NonbenzodiazepineNonbenzodiazepineThe nonbenzodiazepines, also called benzodiazepine-like drugs, are a class of psychoactive drugs pharmacologically resembling the benzodiazepines, with similar benefits, side effects and risks, despite having dissimilar or entirely different chemical structures.-Classes:There are currently three...
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...
, TheanineTheanineTheanine , also gamma-glutamylethylamide or 5-N-ethyl-glutamine, is an amino acid and a glutamic acid analog commonly found in tea , primarily in green tea, and also in the basidiomycete mushroom Boletus badius and in guayusa. More specifically, this compound is called L-theanine, being the...
, Valerenic AcidValerenic acidValerenic acid is a sesquiterpenoid constituent of the essential oil of the Valerian plant. Not to be confused with valeric acid.Valerian is used as a herbal sedative which may be helpful in the treatment of insomnia....
, Volatile/InhaledInhalational 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...
Anesthetics. - Negative Allosteric Modulators: 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...
, 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....
, 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:...
, SarmazenilSarmazenilSarmazenil is a drug from the benzodiazepine family. It acts as a partial inverse agonist of benzodiazepine receptors, meaning that it causes the opposite effects to most benzodiazepine drugs, and instead acts as an anxiogenic and convulsant...
, Zinc . - Non-competitive Channel Blockers: 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....
, 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...
, PentylenetetrazolPentylenetetrazolPentylenetetrazol , also known as metrazol, pentetrazol, pentamethylenetetrazol, Cardiazol or PTZ, is a drug used as a circulatory and respiratory stimulant. High doses cause convulsions, as discovered by the Hungarian-American neurologist and psychiatrist Ladislas J. Meduna in 1934...
, 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" ....
, 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...
, LindaneLindaneLindane, also known as gamma-hexachlorocyclohexane, , gammaxene, Gammallin and erroneously known as benzene hexachloride , is an organochlorine chemical variant of hexachlorocyclohexane that has been used both as an agricultural insecticide and as a pharmaceutical treatment for lice and...
Effects
Ligands which contribute to receptor activation typically have anxiolyticAnxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
, anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
, amnesic, sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
, hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
, euphoriant
Euphoriant
A euphoriant is a type of psychoactive drug which tends to induce feelings of euphoria, the effects of which may include relaxation, anxiolysis, stress relief, mood lift, pleasure, and a rush although these effects are not necessary for a drug to be a euphoriant. Many euphoriants are notorious for...
, and muscle relaxant
Muscle relaxant
A muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics...
properties. Some such as muscimol
Muscimol
Muscimol 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...
may also be hallucinogenic. Ligands which decrease receptor activation usually have opposite effects, including anxiogenesis
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
and convulsion
Convulsion
A convulsion is a medical condition where body muscles contract and relax rapidly and repeatedly, resulting in an uncontrolled shaking of the body. Because a convulsion is often a symptom of an epileptic seizure, the term convulsion is sometimes used as a synonym for seizure...
. Some of the subtype-selective negative allosteric modulators such as α5IA are being investigated for their nootropic
Nootropic
Nootropics , also referred to as smart drugs, brain steroids, memory enhancers, cognitive enhancers, and intelligence enhancers, are drugs, supplements, nutraceuticals, and functional foods that improve mental functions such as cognition, memory, intelligence, motivation, attention, and concentration...
effects, as well as treatments for the unwanted side effects of other GABAergic drugs.
Novel drugs
A useful property of the many benzodiazepine site allosteric modulators is that they may display selective binding to particular subsets of receptors comprising specific subunits. This allows one to determine which GABAA receptor subunit combinations are prevalent in particular brain areas and provides a clue as to which subunit combinations may be responsible for behavioral effects of drugs acting at GABAA receptors. These selective ligands may have pharmacological advantages in that they may allow dissociation of desired therapeutic effects from undesirable side effects. Few subtype selective ligands have gone into clinical use as yet, with the exception of zolpidemZolpidem
Zolpidem is a prescription medication used for the short-term treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class that potentiates gamma-aminobutyric acid , an inhibitory neurotransmitter, by binding to GABAA...
which is reasonably selective for α1, but several more selective compounds are in development such as the α3-selective drug adipiplon
Adipiplon
Adipiplon is an anxiolytic drug developed by Neurogen Corporation. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic....
. There are many examples of subtype-selective compounds which are widely used in scientific research, including:
- CL-218,872CL-218,872CL-218,872 is a sedative and hypnotic drug used in scientific research. It has similar effects to sedative-hypnotic benzodiazepine drugs such as triazolam, but is structurally distinct and so is classed as a nonbenzodiazepine hypnotic....
(highly α1-selective agonist) - bretazenilBretazenilBretazenil is an imidazopyrrolobenzodiazepine anxiolytic drug which is derived from the benzodiazepine family, and was invented in 1988. It is most closely related in structure to the benzodiazepine antagonist flumazenil, although its effects are somewhat different...
(subtype-selective partial agonist) - imidazenilImidazenilImidazenil is an anxiolytic drug which is derived from the benzodiazepine family, and is most closely related to other imidazobenzodiazepines such as midazolam, flumazenil and bretazenil....
and L-838,417L-838,417L-838,417 is an anxiolytic drug used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic...
(both partial agonists at some subtypes, but weak antagonists at others) - QH-ii-066QH-II-66QH-II-66 is a sedative drug which is a benzodiazepine derivative. It produces some of the same effects as other benzodiazepines, but is much more selective than most other drugs of this class and so produces somewhat less sedation and ataxia than other related drugs such as diazepam and triazolam,...
(full agonist highly selective for α5 subtype) - α5IA (selective inverse agonist for α5 subtype)
- SL-651,498SL-651,498SL-651,498 is an anxiolytic and anticonvulsant drug used in scientific research, with a chemical structure most closely related to β-carboline derivatives such as abecarnil and gedocarnil...
(full agonist at α2GABRA2Gamma-aminobutyric acid receptor subunit alpha-2 is a protein that in humans is encoded by the GABRA2 gene....
and α3GABRA3Gamma-aminobutyric acid receptor subunit alpha-3 is a protein that in humans is encoded by the GABRA3 gene.- Function :GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABAA receptors, which are ligand-gated chloride channels...
subtypes, and as a partial agonist at α1GABRA1Gamma-aminobutyric acid receptor subunit alpha-1 is a protein that in humans is encoded by the GABRA1 gene.-Further reading:...
and α5GABRA5Gamma-aminobutyric acid A receptor, alpha 5, also known as GABRA5, is a protein which in humans is encoded by the GABRA5 gene.-Function:... - 3-acyl-4-quinolones: selective for α1 over α3
See also
- GABA receptorGABA receptorThe 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...
- GABAA-ρ receptor
- GABAB receptorGABA B receptorGABAB receptors are metabotropic transmembrane receptors for gamma-aminobutyric acid that are linked via G-proteins to potassium channels...
- Glycine receptorGlycine receptorThe glycine receptor, or GlyR, is the receptor for the amino acid neurotransmitter glycine. GlyR is an ionotropic receptor that produces its effects through chloride current...