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 Na+, K+, Ca2+, and/or Cl− to pass through the membrane in re ...
. Its
endogenous ligand
In coordination chemistry, a ligand is an ion or molecule ( 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 ele ...
is
γ-aminobutyric acid (GABA), the major inhibitory
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neur ...
in the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
. Upon opening, the GABA
A receptor on the
postsynaptic cell
Chemical synapses are biological junctions through which neurons' signals can be sent 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 syste ...
is selectively permeable to
chloride ions (Cl
−) and, to a lesser extent,
bicarbonate ions (HCO
3−). 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. That is, there is a difference in the energy required for electric charge ...
and the ionic concentration difference, this can result in ionic fluxes across the pore. If the membrane potential is higher than the
equilibrium potential (also known as the reversal potential) for chloride ions, when the receptor is activated Cl
− 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 occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...
occurring at the postsynaptic cell. The reversal potential of the GABA
A-mediated
inhibitory postsynaptic potential (IPSP) in normal solution is −70 mV, contrasting the
GABAB IPSP (-100 mV).
The
active site 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), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
s,
nonbenzodiazepines,
neuroactive steroids,
barbiturates,
alcohol (ethanol),
inhaled anaesthetics,
kavalactones,
cicutoxin, and
picrotoxin, among others.
GABA
A receptors occur in all organisms that have a nervous system. To a limited extent the receptors can be found in non-neuronal tissues. Due to their wide distribution within the nervous system of mammals they play a role in virtually all brain functions.
Target for benzodiazepines
The
ionotropic GABA
A receptor protein complex is also the molecular target of the
benzodiazepine
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
class of tranquilizer drugs. Benzodiazepines do not bind to the same receptor ''site'' on the protein complex as the endogenous ligand
GABA (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
neurosteroids 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".
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,
ataxia and
amnesia
Amnesia is a deficit in memory caused by brain damage or disease,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 caused temporarily by the use ...
, whereas those with higher activity at GABA
A receptors containing α2 and/or α3 subunits generally have greater
anxiolytic activity.
Anticonvulsant 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 α
2-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 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 structure of rat α1β1γ2S receptor and human α1β2γ2 receptor bound with GABA and the neutral benzodiazepine flumazenil.
GABA
A receptors are
pentameric
transmembrane receptor
Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integra ...
s which consist of five subunits arranged around a central
pore. 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. ...
of its
neuron
A neuron, neurone, or nerve cell is an membrane potential#Cell excitability, electrically excitable cell (biology), cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous ...
, usually localized at a
synapse
In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell.
Synapses are essential to the transmission of nervous impulses fr ...
, 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
ligand
In coordination chemistry, a ligand is an ion or molecule ( 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 ele ...
GABA is the
endogenous 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 residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
receptor changes conformation within the membrane, opening the pore in order to allow
chloride
The chloride ion is the anion (negatively charged ion) Cl−. It is formed when the element chlorine (a halogen) gains an electron or when a compound such as hydrogen chloride is dissolved in water or other polar solvents. Chloride s ...
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 conve ...
s (Cl
−) and, to a lesser extent,
bicarbonate ions (HCO
3−) to pass down their
electrochemical gradient. 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
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. That is, there is a difference in the energy required for electric charge ...
, activation of GABA
A receptors tends to stabilize or hyperpolarise the resting potential, and can make it more difficult for excitatory
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neur ...
s to
depolarize the neuron and generate an
action potential
An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...
. 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 Cl
− 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 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.
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
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 Na+, K+, Ca2+, and/or Cl− to pass through the membrane in re ...
s that also includes
nicotinic acetylcholine receptors,
glycine receptors, 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 or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...
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
Gamma-aminobutyric acid (GABA) A receptor, alpha 5, also known as GABRA5, is a protein which in humans is encoded by the ''GABRA5'' gene.
Function
GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABAA recept ...
,
GABRA6)
* three βs (
GABRB1,
GABRB2
The GABAA beta-2 subunit is a protein that in humans is encoded by the GABRB2 gene. It combines with other subunits to form the ionotropic GABAA receptors. GABA (γ-aminobutyric acid) system is the major inhibitory system in the brain, and its d ...
,
GABRB3)
* three γs (
GABRG1
Gamma-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 ...
,
GABRG2
Gamma-aminobutyric acid receptor subunit gamma-2 is a protein that in humans is encoded by the ''GABRG2'' gene.
Function
Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain, mediates neuronal inhibition by bindi ...
,
GABRG3)
* as well as a δ (
GABRD), an ε (
GABRE), a π (
GABRP), and a θ (
GABRQ)
There are three ρ units (
GABRR1,
GABRR2
Gamma-aminobutyric acid receptor subunit rho-2 is a protein that in humans is encoded by the ''GABRR2'' gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." mea ...
,
GABRR3); however, these do not coassemble with the classical GABA
A units listed above,
but rather homooligomerize to form
GABAA-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 principles of naming vary from the relatively informal conventions of everyday speech to the internationally agre ...
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 (α
2β
2γ). In neurons themselves, the type of GABA
A receptor subunits and their densities can vary between
cell bodies and
dendrites.
GABA
A receptors can also be found in other tissues, including
leydig cells,
placenta
The placenta is a temporary embryonic and later fetal organ (anatomy), organ that begins embryonic development, developing from the blastocyst shortly after implantation (embryology), implantation. It plays critical roles in facilitating nutrien ...
,
immune cells,
liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
,
bone growth plates and several other
endocrine tissues. Subunit expression varies between 'normal' tissue and
malignancies, as GABA
A receptors can influence
cell proliferation.
Ligands
A number of
ligands 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: bind to the main receptor site (the site where GABA normally binds, also referred to as the "active" or "orthosteric" site). Agonists activate the receptor, resulting in increased Cl
− conductance. Antagonists, though they have no effect on their own, compete with GABA for binding and thereby inhibit its action, resulting in decreased Cl
− conductance.
*
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 Cl
− 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 Cl
− conductance through the ion channel.
Examples
* Orthosteric agonists:
GABA,
gaboxadol,
isoguvacine
Isoguvacine is a GABAA receptor agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, ...
,
muscimol,
progabide
Progabide ( INN; trade name Gabrene, Sanofi-Aventis) is an analogue and prodrug of γ-aminobutyric acid (GABA) used in the treatment of epilepsy. Via conversion into GABA, progabide behaves as an agonist of the GABAA, GABAB, and GABAA-ρ r ...
, beta-alanine,
taurine,
piperidine-4-sulfonic acid (partial agonist).
* Orthosteric antagonists:
bicuculline,
gabazine
Gabazine (SR-95531) 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.
Gabazine binds to the GABA recognition ...
.
* Positive allosteric modulators:
barbiturates,
benzodiazepine
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
s, certain
carbamates (ex.
carisoprodol,
meprobamate,
lorbamate
Lorbamate (INN; Abbott-19,957) is a muscle relaxant and tranquilizer
A tranquilizer is a drug that is designed for the treatment of anxiety, fear, tension, agitation, and disturbances of the mind, specifically to reduce states of anxiety and ...
),
Honokiol,
Magnolol,
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 late ...
,
Baicelin,
thienodiazepines,
alcohol (
ethanol
Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a h ...
),
etomidate,
glutethimide,
kavalactone
Kavalactones are a class of lactone compounds found in kava roots and Alpinia zerumbet (Shell ginger). Kavalactones are under research for potential to have various psychotropic effects, including anxiolytic and sedative/hypnotic activities.
E ...
s,
meprobamate,
quinazolinones (ex.
methaqualone,
etaqualone,
diproqualone),
neuroactive steroids,
[(a) ; (b) ; (c); (d) ; (e) ; (f) ; (g) ; (h) ; (i) ; (j) ; (k) ] niacin/
niacinamide,
nonbenzodiazepines (ex.
zolpidem,
eszopiclone),
propofol
Propofol, marketed as Diprivan, among other names, is a short-acting medication that results in a decreased level of consciousness and a lack of memory for events. Its uses include the starting and maintenance of general anesthesia, sedation ...
,
stiripentol,
theanine,
valerenic acid,
volatile/inhaled anesthetics,
lanthanum, and
riluzole.
* Negative allosteric modulators:
flumazenil,
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 with the symbol Zn and atomic number 30. Zinc 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 t ...
.
* Inverse allosteric agonists:
beta-carbolines (ex.
Harmine,
Harmaline,
Tetrahydroharmine).
* Second-order modulators:
(−)‐epigallocatechin‐3‐gallate.
* Non-competitive channel blockers:
cicutoxin,
oenanthotoxin,
pentylenetetrazol,
picrotoxin,
thujone, and
lindane
Lindane, also known as ''gamma''-hexachlorocyclohexane (γ-HCH), gammaxene, Gammallin and benzene hexachloride (BHC), is an organochlorine chemical and an isomer of hexachlorocyclohexane that has been used both as an agricultural insecticide and ...
.
Effects
Ligands which contribute to receptor activation typically have
anxiolytic,
anticonvulsant,
amnesic,
sedative
A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but ...
,
hypnotic
Hypnotic (from Greek ''Hypnos'', sleep), or soporific drugs, commonly known as sleeping pills, are a class of (and umbrella term for) psychoactive drugs whose primary function is to induce sleep (or surgical anesthesiaWhen used in anesthesia ...
,
euphoriant, and
muscle relaxant properties. Some such as
muscimol and the
z-drugs may also be
hallucinogenic
Hallucinogens are a large, diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mood, and perception as well as other changes. Most hallucinogens can be categorize ...
. 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 sometimes used as a ...
. Some of the subtype-selective negative allosteric modulators such as
α5IA are being investigated for their
nootropic
Nootropics ( , or ) ( colloquial: smart drugs and cognitive enhancers, similar to adaptogens) are a wide range of natural or synthetic supplements or drugs and other substances that are claimed to improve cognitive function or to promote re ...
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 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
zolpidem which is reasonably selective for α
1, but several more selective compounds are in development such as the α
3-selective drug
adipiplon. There are many examples of subtype-selective compounds which are widely used in scientific research, including:
*
CL-218,872
CL-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.
CL-218 ...
(highly α
1-selective agonist)
*
bretazenil
Bretazenil (Ro16-6028) 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 GABA antagonist flumazenil, although its effects a ...
(subtype-selective partial agonist)
*
imidazenil
Imidazenil is an experimental anxiolytic drug which is derived from the benzodiazepine family, and is most closely related to other imidazobenzodiazepines such as midazolam, flumazenil, and bretazenil.
Imidazenil is a highly potent benzodiaze ...
and
L-838,417 (both partial agonists at some subtypes, but weak antagonists at others)
*
QH-ii-066 (full agonist highly selective for α
5 subtype)
*
α5IA (selective inverse agonist for α
5 subtype)
*
SL-651,498 (full agonist at
α2 and
α3 subtypes, and as a partial agonist at
α1 and
α5
* 3-acyl-4-quinolones: selective for α
1 over α
3
Paradoxical reactions
There are multiple indications that
paradoxical reactions upon – for example – benzodiazepines, barbiturates,
inhalational anesthetics,
propofol
Propofol, marketed as Diprivan, among other names, is a short-acting medication that results in a decreased level of consciousness and a lack of memory for events. Its uses include the starting and maintenance of general anesthesia, sedation ...
,
neurosteroids, and
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
genetic and also
epigenetic
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are " ...
deviations. There are indication that the latter may be triggered by, among other factors,
social stress or
occupational burnout
According to the World Health Organization (WHO), occupational burnout is a syndrome resulting from chronic work-related stress, with symptoms characterized by "feelings of energy depletion or exhaustion; increased mental distance from one’ ...
.
See also
*
4-Iodopropofol
*
GABA receptor
*
GABAB receptor
*
GABAA-ρ receptor
*
Gephyrin
*
Glycine receptor
*
GABAA receptor positive allosteric modulators
*
GABAA receptor negative allosteric modulators
References
Further reading
*
*
*
*
External links
*
{{DEFAULTSORT:Gabaa Receptor
Transmembrane receptors
Ion channels
GABA