The GABA_A receptor (GABA_AR) is an ionotropic receptor and

ligand-gated ion channel Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as sodium, Na+, potassium, K+, calcium, Ca2+, and/or chloride, Cl− to ...

. Its

endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

γ-aminobutyric acid GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

(GABA), the major inhibitory

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

. Accurate regulation of GABAergic transmission through appropriate developmental processes, specificity to neural cell types, and responsiveness to activity is crucial for the proper functioning of nearly all aspects of the central nervous system (CNS). Upon opening, the GABA_A receptor on the postsynaptic cell is selectively permeable to chloride ions () and, to a lesser extent, bicarbonate ions (). GABA_AR are members of the ligand-gated ion channel receptor superfamily, which is a chloride channel family with a dozen or more heterotetrametric subtypes and 19 distinct subunits. These subtypes have distinct brain regional and subcellular localization, age-dependent expression, and the ability to undergo plastic alterations in response to experience, including drug exposure. GABA_AR is not just the target of agonist depressants and antagonist convulsants, but most GABA_AR medicines also act at additional (allosteric) binding sites on GABA_AR proteins. Some sedatives and anxiolytics, such as benzodiazepines and related medicines, act on GABA_AR subtype-dependent extracellular domain sites. Alcohols and neurosteroids, among other general anesthetics, act at GABA_AR subunit-interface transmembrane locations. High anesthetic dosages of ethanol act on GABA_AR subtype-dependent transmembrane domain locations. Ethanol acts at GABA_AR subtype-dependent extracellular domain locations at low intoxication concentrations. Thus, GABA_AR subtypes have pharmacologically distinct receptor binding sites for a diverse range of therapeutically significant neuropharmacological drugs. Depending on the

membrane potential Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. It equals the interior potential minus the exterior potential. This is th ...

and the ionic concentration difference, this can result in ionic fluxes across the pore. If the membrane potential is higher than the

equilibrium potential In a biological membrane, the reversal potential is the membrane potential at which the direction of ionic current reverses. At the reversal potential, there is no net flow of ions from one side of the membrane to the other. For channels that are pe ...

(also known as the reversal potential) for chloride ions, when the receptor is activated will flow into the cell. This causes an inhibitory effect on

neurotransmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron ...

by diminishing the chance of a successful

action potential An action potential (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific Cell (biology), cell rapidly ri ...

occurring at the postsynaptic cell. The reversal potential of the GABA_A-mediated

inhibitory postsynaptic potential An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential.Purves et al. Neuroscience. 4th ed. Sunderland (MA): Sinauer Associates, Incorporated; 2008. ...

(IPSP) in normal solution is −70 mV, contrasting the GABA_B IPSP (−100 mV). The

active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate, the ''binding s ...

of the GABA_A receptor is the binding site for GABA and several drugs such as muscimol, gaboxadol, and bicuculline. 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 Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

nonbenzodiazepine Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive, depressant, sedative, hypnotic, anxiolytic drugs that are benzodiazepine-like in uses, such as f ...

neuroactive steroid Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term ''neurosteroid'' was coi ...

barbiturate Barbiturates are a class of depressant, depressant drugs that are chemically derived from barbituric acid. They are effective when used medication, medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological a ...

alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

(ethanol), inhaled anaesthetics, kavalactones,

cicutoxin Cicutoxin is a naturally-occurring poisonous chemical compound produced by several plants from the family Apiaceae including water hemlock ('' Cicuta'' species) and water dropwort (''Oenanthe crocata''). The compound contains polyene, polyyn ...

, and picrotoxin, among others. Binding of GABA to the GABAAR causes the receptor to shift from ordered lipids to clusters of PIP2 in the disordered region of the membrane. The spatial distribution of GABAAR in neurons is regulated by astrocyte derived cholesterol. Much like the GABA_A receptor, the GABA_B receptor is an obligatory heterodimer consisting of GABA_B1 and GABA_B2 subunits. These subunits include an extracellular Venus Flytrap domain (VFT) and a transmembrane domain containing seven α-helices (7TM domain). These structural components play a vital role in intricately modulating neurotransmission and interactions with drugs.

Target for benzodiazepines

The

ionotropic Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in res ...

GABA_A receptor protein complex is also the molecular target of the

class of tranquilizer drugs. Benzodiazepines do not bind to the same receptor ''site'' on the protein complex as does the endogenous ligand

GABA GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

(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 GABA_A receptors. While the majority of GABA_A receptors (those containing α1-, α2-, α3-, or α5-subunits) are benzodiazepine sensitive, there exists a minority of GABA_A 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

neurosteroid Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term ''neurosteroid'' was coi ...

s and alcohol. In addition peripheral benzodiazepine receptors exist which are not associated with GABA_A receptors. As a result, the IUPHAR 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". Benzodiazepines like diazepam and midazolam act as positive allosteric modulators for GABA_A receptors. When these receptors are activated, there's a rise in intracellular chloride levels, resulting in cell membrane hyperpolarization and decreased excitation. In order for GABA_A receptors to be sensitive to the action of benzodiazepines they need to contain an α and a γ subunit, between which the benzodiazepine binds. Once bound, the benzodiazepine locks the GABA_A receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABA_A 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 sedative and anxiolytic effects. Different benzodiazepines have different affinities for GABA_A 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 is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...

ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...

and

amnesia Amnesia is a deficit in memory caused by brain damage or brain diseases,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be temporarily caused by t ...

, whereas those with higher activity at GABA_A receptors containing α2 and/or α3 subunits generally have greater

anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

activity.

Anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...

effects can be produced by agonists acting at any of the GABA_A 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 Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as ...

and GABA on the GABA_A receptor, and also produces different effects on binding, with the benzodiazepines increasing the frequency of the chloride channel opening, while barbiturates increase the duration of chloride channel opening when GABA is bound. 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 GABA_A agonists such as muscimol and gaboxadol do bind to the same site on the GABA_A 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

Structural understanding of the GABA_A receptor was initially based on homology models, obtained using crystal structures of homologous proteins like Acetylcholine binding protein (AChBP) and nicotinic acetylcholine (nACh) receptors as templates. The much sought structure of a GABA_A receptor was finally resolved, with the disclosure of the crystal structure of human β3 homopentameric GABA_A receptor. Whilst this was a major development, the majority of GABA_A receptors are heteromeric and the structure did not provide any details of the benzodiazepine binding site. This was finally elucidated in 2018 by the publication of a high resolution

cryo-EM Cryogenic electron microscopy (cryo-EM) is a transmission electron microscopy technique applied to samples cooled to cryogenic temperatures. For biological specimens, the structure is preserved by embedding in an environment of vitreous ice. An ...

structure of rat α1β1γ2S receptor and human α1β2γ2 receptor bound with GABA and the neutral benzodiazepine flumazenil. GABA_A receptors are

pentamer A pentamer is an entity composed of five subunits. In chemistry, it applies to molecules made of five monomers. In biochemistry, it applies to macromolecules, particularly pentameric proteins, made of five protein sub-units. In microbiology, a ...

transmembrane receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptor (biochemistry), receptors that are embedded in the cell membrane, plasma membrane of cell (biology), cells. They act in cell signaling by receiving (binding to) ex ...

s which consist of five subunits arranged around a central

pore Pore may refer to: Biology Animal biology and microbiology * Sweat pore, an anatomical structure of the skin of humans (and other mammals) used for secretion of sweat * Hair follicle, an anatomical structure of the skin of humans (and other ...

. Each subunit comprises four transmembrane domains with both the N- and C-terminus located extracellularly. The receptor sits in the

membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. Bi ...

of its

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

, usually localized at a

synapse In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...

, postsynaptically. However, some isoforms may be found extrasynaptically. When vesicles of GABA are released presynaptically and activate the GABA receptors at the synapse, this is known as phasic inhibition. However, the GABA escaping from the synaptic cleft can activate receptors on presynaptic terminals or at neighbouring synapses on the same or adjacent neurons (a phenomenon termed 'spillover') in addition to the constant, low GABA concentrations in the extracellular space results in persistent activation of the GABA_A receptors known as tonic inhibition. The

GABA is the

compound that causes this receptor to open; once bound to GABA, the

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

receptor changes conformation within the membrane, opening the pore in order to allow

chloride The term chloride refers to a compound or molecule that contains either a chlorine anion (), which is a negatively charged chlorine atom, or a non-charged chlorine atom covalently bonded to the rest of the molecule by a single bond (). The pr ...

anion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...

s () and, to a lesser extent, bicarbonate ions () to pass down their

electrochemical gradient An electrochemical gradient is a gradient of electrochemical potential, usually for an ion that can move across a membrane. The gradient consists of two parts: * The chemical gradient, or difference in Concentration, solute concentration across ...

. The binding site to GABA is about 80Å away from the narrowest part of the ion channel. Recent computational studies have suggested an allosteric mechanism whereby GABA binding leads to ion channel opening. Because the reversal potential for chloride in most mature neurons is close to or more negative than the resting

, activation of GABA_A receptors tends to stabilize or hyperpolarise the resting potential, and can make it more difficult for excitatory

s to depolarize the neuron and generate an

. The net effect therefore typically inhibitory, reducing the activity of the neuron, although depolarizing currents have been observed in response to GABA in immature neurons in early development. This effect during development is due to a modified gradient wherein the anions leave the cells through the GABA_A receptors, since their intracellular chlorine concentration is higher than the extracellular. The difference in extracellular chlorine anion concentration is presumed to be due to the higher activity of chloride transporters, such as NKCC1, transporting chloride into cells which are present early in development, whereas, for instance, KCC2 transports chloride out of cells and is the dominant factor in establishing the chloride gradient later in development. These depolarization events have shown to be key in neuronal development. In the mature neuron, the GABA_A 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. Proper developmental, neuronal cell-type-specific, and activity-dependent GABAergic transmission control is required for nearly all aspects of CNS function. It has been proposed that the GABAergic system is disrupted in numerous neurodevelopmental diseases, including fragile X syndrome, Rett syndrome, and Dravet syndrome, and that it is a crucial potential target for therapeutic intervention.

Subunits

GABA_A receptors are members of the large pentameric ligand gated ion channel (previously referred to as "''Cys''-loop" receptors) super-family of evolutionarily related and structurally similar

s that also includes

nicotinic acetylcholine receptor Nicotinic acetylcholine receptors, or nAChRs, are Receptor (biochemistry), receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the c ...

glycine receptor The glycine receptor (abbreviated as GlyR or GLR) is the receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochem ...

s, and the 5HT₃ receptor. There are numerous subunit

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

s for the GABA_A 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 ( GABRA1, GABRA2, GABRA3, GABRA4, GABRA5, GABRA6) * three βs ( GABRB1, GABRB2,

GABRB3 Gamma-aminobutyric acid receptor subunit beta-3 is a protein that in humans is encoded by the ''GABRB3'' gene. It is located within the 15q12 region in the human genome and spans 250kb. This gene includes 10 exons within its coding region. Due to ...

) * three γs ( GABRG1, GABRG2, GABRG3) * as well as a δ (

GABRD Gamma-aminobutyric acid receptor subunit delta is a protein that in humans is encoded by the ''GABRD'' gene. In the mammalian brain, the delta (δ) subunit forms specific GABAA receptor subtypes by co-assembly leading to δ subunit containing GA ...

), an ε ( GABRE), a π ( GABRP), and a θ ( GABRQ) There are three ρ units ( GABRR1, GABRR2, GABRR3); however, these do not coassemble with the classical GABA_A units listed above, but rather homooligomerize to form GABA_A-ρ receptors (formerly classified as GABA_C receptors but now this

nomenclature Nomenclature (, ) is a system of names or terms, or the rules for forming these terms in a particular field of arts or sciences. (The theoretical field studying nomenclature is sometimes referred to as ''onymology'' or ''taxonymy'' ). The principl ...

has been deprecated).

Combinatorial arrays

Given the large number of GABA_A receptors, a great diversity of final pentameric receptor subtypes is possible. Methods to produce cell-based laboratory access to a greater number of possible GABA_A receptor subunit combinations allow teasing apart of the contribution of specific receptor subtypes and their physiological and pathophysiological function and role in the CNS and in disease.

Distribution

GABA_A receptors are responsible for most of the physiological activities of GABA in the central nervous system, and the receptor subtypes vary significantly. Subunit composition can vary widely between regions and subtypes may be associated with specific functions. The minimal requirement to produce a GABA-gated ion channel is the inclusion of an α and a β subunit. The most common GABA_A receptor is a pentamer comprising two α's, two β's, and a γ (α₂β₂γ). In neurons themselves, the type of GABA_A receptor subunits and their densities can vary between cell bodies and

dendrites A dendrite (from Greek δένδρον ''déndron'', "tree") or dendron is a branched cytoplasmic process that extends from a nerve cell that propagates the electrochemical stimulation received from other neural cells to the cell body, or soma ...

. Benzodiazepines and barbiturates amplify the inhibitory effects mediated by the GABAA receptor. GABA_A receptors can also be found in other tissues, including

leydig cells Leydig cells, also known as interstitial cells of the testes and interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle and produce testosterone in the presence of luteinizing hormone (LH). They are polyhedral ...

placenta The placenta (: placentas or placentae) is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas, and waste exchange between ...

immune cells White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

, bone growth plates and several other endocrine tissues. Subunit expression varies between 'normal' tissue and

malignancies Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not ...

, as GABA_A receptors can influence

cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation ...

Ligands

A number of

ligands In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ...

have been found to bind to various sites on the GABA_A receptor complex and modulate it besides GABA itself. A ligand can possess one or more properties of the following types. Unfortunately the literature often does not distinguish these types properly.

Types

* Orthosteric agonists and

antagonists An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.First order allosteric modulators: bind to allosteric sites on the receptor complex and affect it either in a positive (PAM), negative (NAM) or neutral/silent (SAM) manner, causing increased or decreased efficiency of the main site and therefore an indirect increase or decrease in conductance. SAMs do not affect the conductance, but occupy the binding site. * Second order modulators: bind to an allosteric site on the receptor complex and modulate the effect of first order modulators. * Open channel blockers: prolong ligand-receptor occupancy, activation kinetics and Cl ion flux in a subunit configuration-dependent and sensitization-state dependent manner. * Non-competitive channel blockers: bind to or near the central pore of the receptor complex and directly block conductance through the ion channel.

Examples

* Orthosteric agonists:

, gaboxadol, isoguvacine, muscimol, progabide, beta-alanine,

taurine Taurine (), or 2-aminoethanesulfonic acid, is a naturally occurring amino sulfonic acid that is widely distributed in animal tissues. It is a major constituent of bile and can be found in the large intestine. It is named after Latin (cogna ...

, piperidine-4-sulfonic acid (partial agonist). * Orthosteric antagonists: bicuculline, gabazine. * Positive allosteric modulators: abecarnil, azocarnil ( photoswitchable),

s, certain

carbamates In organic chemistry, a carbamate is a category of organic compounds with the general formula and structure , which are formally derived from carbamic acid (). The term includes organic compounds (e.g., the ester ethyl carbamate), formally obt ...

(e.g.,

carisoprodol Carisoprodol, sold under the brand name Soma among others, is an oral medication used for musculoskeletal pain. Effects generally begin within half an hour and last for up to six hours. Common side effects include headache, dizziness, and s ...

meprobamate Meprobamate—marketed as Miltown by Wallace Laboratories and Equanil by Wyeth, among others—is a carbamate derivative used as an anxiolytic drug. It was the best-selling minor tranquilizer for a time, but has largely been replaced by the benz ...

, lorbamate),

honokiol Honokiol is a lignan Bark isolate, isolated from the bark, seed cones, and leaves of trees belonging to the genus ''Magnolia''. It has been identified as one of the chemical compounds in some traditional Eastern herbal medicines along with magnolo ...

magnolol Magnolol is an organic compound that is classified as lignan. It is a bioactive compound found in the bark of the Houpu magnolia ('' Magnolia officinalis'') and in '' M. grandiflora''. Magnolol is a compound that acts on GABA_A receptors and fu ...

baicalin As baicalin is a flavone glycoside, it is a flavonoid. It is the glucuronide of baicalein. Natural occurrences Baicalin is found in several species in the genus ''Scutellaria'', including ''Scutellaria baicalensis'', and ''Scutellaria laterifl ...

, baicelin,

thienodiazepine A thienodiazepine is a heterocyclic compound containing a diazepine ring fused to a thiophene ring. If R1 and R2 are part of a triazole ring, the substance is called a "thienotriazolodiazepine." The thienodiazepine structure forms the central ...

(

ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...

etomidate Etomidate (United States Adopted Name, USAN, International Nonproprietary Name, INN, British Approved Name, BAN; marketed as Amidate) is a short-acting intravenous anaesthetic agent used for the induction of general anaesthesia and sedation for ...

glutethimide Glutethimide (brand names included Doriden, Elrodorm, and Noxyrom) is a central nervous system (CNS) depressant drug of the piperidine chemical class, one of many non-barbiturate, "barbiturate-like" GABAergic medications exhibiting general calm ...

kavalactone Kavalactones are a class of lactone compounds found in kava roots and ''Alpinia zerumbet'' (shell ginger) and in several Gymnopilus, Phellinus and Inonotus fungi. Some kavalactones are bioactive. They are responsible for the psychoactive, analges ...

quinazolinone Quinazolinone is a heterocyclic chemical compound, a quinazoline with a carbonyl group in the C4N2 ring. Two isomers are possible: 2-quinazolinone and 4-quinazolinone, with the 4-isomer being the more common. These compounds are of interest in ...

s (e.g.,

methaqualone Methaqualone is a hypnotic sedative. It was sold under the brand names Quaalude ( ) and Sopor among others, which contained 300 mg of methaqualone, and sold as a combination drug under the brand name Mandrax, which contained 250 mg me ...

etaqualone Etaqualone (Aolan, Athinazone, Ethinazone) is a quinazolinone-class GABAergic and is an analogue of methaqualone that was developed in the 1960s. It was primarily marketed in France and other European countries, as well as later in China, where ...

diproqualone Diproqualone is a quinazolinone class GABAergic and is an analogue of methaqualone developed in the late 1950s by a team at Nogentaise de Produits Chimique. It was marketed primarily in France and some other European countries. It has sedative ...

s,(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h)
(i)
(j)
(k) niacin/ niacinamide,

s (e.g.,

zolpidem Zolpidem, sold under the brand name Ambien among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and after beh ...

eszopiclone Eszopiclone, sold under the brand name Lunesta among others, is a nonbenzodiazepine medication used in the treatment of short-term and long-term insomnia. It holds the distinction of being one of the few FDA-approved hypnotic medications with ...

propofol Propofol is the active component of an intravenous anesthetic formulation used for induction and maintenance of general anesthesia. It is chemically termed 2,6-diisopropylphenol. The formulation was approved under the brand name Diprivan. Nu ...

stiripentol Stiripentol, sold under the brand name Diacomit, is an anticonvulsant medication used for the treatment of Dravet syndrome - a serious genetic brain disorder. The most common side effects include loss of appetite, weight loss, insomnia (difficu ...

theanine Theanine , also known as L-theanine, L-gamma-glutamylethylamide, or ''N''5-ethyl-L-glutamine, is a non-proteinogenic amino acid similar to the proteinogenic amino acids glutamic acid, L-glutamate and glutamine, L-glutamine. It is produced by ce ...

, valerenic acid, volatile/inhaled

anesthetic An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into t ...

lanthanum Lanthanum is a chemical element; it has symbol La and atomic number 57. It is a soft, ductile, silvery-white metal that tarnishes slowly when exposed to air. It is the eponym of the lanthanide series, a group of 15 similar elements bet ...

, riluzole, and

menthol Menthol is an organic compound, specifically a Monoterpene, monoterpenoid, that occurs naturally in the oils of several plants in the Mentha, mint family, such as Mentha arvensis, corn mint and peppermint. It is a white or clear waxy crystallin ...

. * Negative allosteric modulators:

flumazenil Flumazenil, also known as flumazepil, is a selective GABAA receptor, GABAA receptor antagonist administered via injection, otic insertion, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines (partic ...

, Ro15-4513,

sarmazenil Sarmazenil (Ro15-3505) 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 con ...

, pregnenolone sulfate, amentoflavone, and

zinc Zinc is a chemical element; it has symbol Zn and atomic number 30. It is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic tabl ...

. * Inverse allosteric agonists: beta-carbolines (e.g., harmine, harmaline, tetrahydroharmine). * Second-order modulators: (−)‐epigallocatechin‐3‐gallate. * Non-competitive channel blockers:

, oenanthotoxin, pentylenetetrazol, picrotoxin,

thujone Thujone () is a ketone and a terpene, monoterpene that occurs predominantly in two diastereomeric (epimeric) forms: (−)-α-thujone and (+)-β-thujone. Though it is best known as a chemical compound in the spirit absinthe, it is only present in ...

, and lindane.

Effects

Ligands which contribute to receptor activation typically have

anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...

, amnesic,

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...

hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...

, euphoriant, and

muscle relaxant A muscle relaxant is a drug that 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 therapeu ...

properties. Some such as muscimol and the

z-drugs Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive, depressant, sedative, hypnotic, anxiolytic drugs that are benzodiazepine-like in uses, such as f ...

may also be hallucinogenic. Ligands which decrease receptor activation usually have opposite effects, including anxiogenesis and

convulsion A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is often used as a synony ...

. Some of the subtype-selective negative allosteric modulators such as α₅IA are being investigated for their

nootropic Nootropics ( or ) (colloquially brain supplements, smart drugs, cognitive enhancers, memory enhancers, or brain boosters) are chemical substances which purportedly improve cognitive functions, such as attention, memory, wakefulness, and self ...

effects, as well as treatments for the unwanted side effects of other GABAergic drugs. Advances in molecular pharmacology and genetic manipulation of rat genes have revealed that distinct subtypes of the GABA_A receptor mediate certain parts of the anaesthetic behavioral repertoire.

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 GABA_A 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 GABA_A 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

which is reasonably selective for α₁, but several more selective compounds are in development such as the α₃-selective drug adipiplon. There are many examples of subtype-selective compounds which are widely used in scientific research, including: * CL-218,872 (highly α₁-selective agonist) * bretazenil (subtype-selective partial agonist) * imidazenil and L-838,417 (both partial agonists at some subtypes, but weak antagonists at others) * QH-II-66, QH-ii-066 (full agonist highly selective for α₅ subtype) * α₅IA (selective inverse agonist for α₅ subtype) * SL-651,498 (full agonist at GABRA2, α₂ and GABRA3, α₃ subtypes, and as a partial agonist at GABRA1, α₁ and GABRA5, α₅ * 3-acyl-4-quinolones: selective for α₁ over α₃

Paradoxical reactions

There are multiple indications that paradoxical reactions upon — for example — benzodiazepines, barbiturates, inhalational anesthetics,

s, and Alcohol (drug), alcohol are associated with structural deviations of GABA_A receptors. The combination of the five subunits of the receptor (see images above) can be altered in such a way that for example the receptor's response to GABA remains unchanged but the response to one of the named substances is dramatically different from the normal one. There are estimates that about 2–3% of the general population may suffer from serious emotional disorders due to such receptor deviations, with up to 20% suffering from moderate disorders of this kind. It is generally assumed that the receptor alterations are, at least partly, due to Genetics, genetic and also Epigenetics, epigenetic deviations. There are indication that the latter may be triggered by, among other factors, social stress or occupational burnout.

References

External links

* {{DEFAULTSORT:Gabaa Receptor Transmembrane receptors Ion channels GABA