![Fig-GABAA receptor](https://upload.wikimedia.org/wikipedia/commons/1/15/Fig-GABAA_receptor.png)
The GABA
A receptor (GABA
AR) is an
ionotropic receptor
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 ...
and
ligand-gated ion channel. Its
endogenous
Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell.
In contrast, exogenous substances and processes are those that originate from outside of an organism.
For example, es ...
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 electr ...
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.
Neuro ...
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 par ...
. 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
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 salts ...
(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 charges ...
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 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
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 (binding site) a ...
of the GABA
A receptor is the binding site for GABA and several drugs such as
muscimol,
gaboxadol
Gaboxadol, also known as 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), is a conformationally constrained derivative of the alkaloid muscimol that was first synthesized in 1977 by the Danish chemist Povl Krogsgaard-Larsen. In the early 19 ...
, and
bicuculline
Bicuculline is a phthalide-isoquinoline compound that 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 ...
.
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,
nonbenzodiazepine
Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep proble ...
s,
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 coin ...
s,
barbiturate
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 we ...
s,
alcohol
Alcohol most commonly refers to:
* Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom
* Alcohol (drug), an intoxicant found in alcoholic drinks
Alcohol may also refer to:
Chemicals
* Ethanol, one of sev ...
(ethanol),
inhaled anaesthetics,
kavalactones
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.
Enzym ...
,
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, polyyne ...
, 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
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 coin ...
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".
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 is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...
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
Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...
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
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
Gaboxadol, also known as 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), is a conformationally constrained derivative of the alkaloid muscimol that was first synthesized in 1977 by the Danish chemist Povl Krogsgaard-Larsen. In the early 19 ...
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
![GABAA-receptor-protein-example](https://upload.wikimedia.org/wikipedia/commons/4/45/GABAA-receptor-protein-example.png)
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
pentamer
A pentamer is an entity composed of five sub-units.
In chemistry, it applies to molecules made of five monomers.
In biochemistry, it applies to macromolecules, in particular to pentameric proteins, made of five proteic sub-units.
In microbiolog ...
ic
transmembrane receptors 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 of its
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
, 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 from ...
, postsynaptically. However, some isoforms may be found extrasynaptically. When
vesicles
Vesicle may refer to:
; In cellular biology or chemistry
* Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane
* Synaptic vesicle
; In human embryology
* Vesicle (embryology), bulge-like features o ...
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 electr ...
GABA is the
endogenous
Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell.
In contrast, exogenous substances and processes are those that originate from outside of an organism.
For example, es ...
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, respo ...
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 salts ...
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 convent ...
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 charges ...
, 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.
Neuro ...
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
The Na-K-Cl cotransporter (NKCC) is a protein that aids in the secondary active transport of sodium, potassium, and chloride into cells. In humans there are two isoforms of this membrane transport protein, NKCC1 and NKCC2, encoded by two differ ...
, transporting chloride into cells which are present early in development, whereas, for instance,
KCC2
Potassium-chloride transporter member 5 (aka: KCC2 and SLC12A5) is a neuron-specific chloride potassium symporter responsible for establishing the chloride ion gradient in neurons through the maintenance of low intracellular chloride concentratio ...
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 channels that also includes
nicotinic acetylcholine receptors,
glycine receptor
The glycine receptor (abbreviated as GlyR or GLR) is the receptor of the amino acid neurotransmitter glycine. GlyR is an ionotropic receptor that produces its effects through chloride current. It is one of the most widely distributed inhibitory ...
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 or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
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
Gamma-aminobutyric acid receptor subunit alpha-1 is a protein that in humans is encoded by the ''GABRA1'' gene.
GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chlor ...
,
GABRA2
Gamma-aminobutyric acid receptor subunit alpha-2 is a protein in humans that is encoded by the ''GABRA2'' gene.
GABRA2 is an alpha subunit that is part of GABA-A receptors, which are ligand-gated chloride channels and are activated by the majo ...
,
GABRA3
Gamma-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- ...
,
GABRA4
Gamma-aminobutyric acid receptor subunit alpha-4 is a protein that in humans is encoded by the ''GABRA4'' gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." m ...
,
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
gamma-aminobutyric acid, GABA is the major inhibitory neurotransmitter in the mammalian brain where ...
,
GABRA6
Gamma-aminobutyric acid receptor subunit alpha-6 is a protein that in humans is encoded by the ''GABRA6'' gene.
GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chlorid ...
)
* three βs (
GABRB1
Gamma-aminobutyric acid receptor subunit beta-1 is a protein that in humans is encoded by the ''GABRB1'' gene.
Function
The gamma-aminobutyric acid A receptor ( GABAA receptor) is a multisubunit chloride channel that mediates the fastest inhibi ...
,
GABRB2
The GABAA beta-2 subunit is a protein that in humans is encoded by the GABRB2 gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or '' ...
,
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 a ...
)
* three γs (
GABRG1,
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 binding ...
,
GABRG3
GABAA 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 ( GABA).
Association with alcoholism ...
)
* 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 GABA ...
), an ε (
GABRE
Gamma-aminobutyric acid receptor subunit epsilon is a protein that in humans is encoded by the ''GABRE'' gene.
The product of this gene belongs to the ligand-gated ionic channel (TC 1.A.9) family. It encodes the gamma-aminobutyric acid (GABA) A r ...
), a π (
GABRP
Gamma-aminobutyric acid receptor subunit pi is a protein that in humans is encoded by the ''GABRP'' gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meanin ...
), and a θ (
GABRQ
Gamma-aminobutyric acid receptor subunit theta is a protein that in humans is encoded by the ''GABRQ'' gene. The protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. P ...
)
There are three ρ units (
GABRR1
Gamma-aminobutyric acid receptor subunit rho-1 is a protein that in humans is encoded by the ''GABRR1'' gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." mea ...
,
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
Gamma-aminobutyric acid receptor subunit rho-3 is a protein that in humans is encoded by the ''GABRR3'' gene. The protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Pr ...
); 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 naming conventions, conventions of everyday speech to the i ...
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
The soma (pl. ''somata'' or ''somas''), perikaryon (pl. ''perikarya''), neurocyton, or cell body is the bulbous, non-process portion of a neuron or other brain cell type, containing the cell nucleus. The word 'soma' comes from the Greek '' σῶ ...
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 that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mater ...
,
immune cells
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
,
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
,
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.
Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...
, 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 re ...
.
Ligands
![GABAa receptor](https://upload.wikimedia.org/wikipedia/commons/3/3a/GABAa_receptor.gif)
A number of
ligands
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 electro ...
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 chief foe of the protagonist.
Etymology
The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
: 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
Gaboxadol, also known as 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), is a conformationally constrained derivative of the alkaloid muscimol that was first synthesized in 1977 by the Danish chemist Povl Krogsgaard-Larsen. In the early 19 ...
,
isoguvacine
Isoguvacine is a GABAA receptor agonist used in scientific research.
See also
* Gaboxadol
* Muscimol
Muscimol (also known as agarin or pantherine) is one of the principal psychoactive constituents of '' Amanita muscaria'' and related specie ...
,
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 re ...
, beta-alanine,
taurine,
piperidine-4-sulfonic acid (partial agonist).
* Orthosteric antagonists:
bicuculline
Bicuculline is a phthalide-isoquinoline compound that 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 ...
,
gabazine
Gabazine (SR-95531) is a drug that acts as an Receptor antagonist, antagonist at GABAA receptor, GABAA Receptor (biochemistry), receptors. It is used in scientific research and has no role in medicine, as it would be expected to produce convulsio ...
.
* Positive allosteric modulators:
barbiturate
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 we ...
s,
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
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 obta ...
(ex.
carisoprodol
Carisoprodol, sold under the brand name Soma among others, is a medication used for musculoskeletal pain. Use is only approved for up to three weeks. Effects generally begin within half an hour and last for up to six hours. It is taken orally.
...
,
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 lateri ...
,
Baicelin,
thienodiazepine
A thienodiazepine is a heterocyclic compound containing a diazepine ring fused to a thiophene
Thiophene is a heterocyclic compound with the formula C4H4S. Consisting of a planar five-membered ring, it is aromatic as indicated by its extens ...
s,
alcohol
Alcohol most commonly refers to:
* Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom
* Alcohol (drug), an intoxicant found in alcoholic drinks
Alcohol may also refer to:
Chemicals
* Ethanol, one of sev ...
(
ethanol
Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an Alcohol (chemistry), alcohol with the chemical formula . Its formula can be also written as or (an ethyl ...
),
etomidate
Etomidate (USAN, INN, BAN; marketed as Amidate) is a short-acting intravenous anaesthetic agent used for the induction of general anaesthesia and sedation for short procedures such as reduction of dislocated joints, tracheal intubation, cardiove ...
,
glutethimide
Glutethimide is a hypnotic sedative that was introduced by Ciba 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 simila ...
,
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.
En ...
s,
meprobamate,
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 med ...
s (ex.
methaqualone,
etaqualone
Etaqualone (Aolan, Athinazone, Ethinazone) is a quinazolinone-class GABAergic and is an analogue of methaqualone that was developed in the 1960s and marketed mainly in France and some other European countries. It has sedative, hypnotic, muscle ...
,
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, a ...
),
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 coin ...
s,
[(a) ; (b) ; (c); (d) ; (e) ; (f) ; (g) ; (h) ; (i) ; (j) ; (k) ] niacin
Niacin, also known as nicotinic acid, is an organic compound and a form of vitamin B3, an essential human nutrient. It can be manufactured by plants and animals from the amino acid tryptophan. Niacin is obtained in the diet from a variet ...
/
niacinamide,
nonbenzodiazepine
Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep proble ...
s (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 f ...
,
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,
valerenic acid
Valerenic acid is a sesquiterpenoid constituent of the essential oil of the valerian plant.
Valerian is used as a herbal sedative which may be helpful in the treatment of insomnia. Valerenic acid may be at least partly responsible for valeri ...
,
volatile/inhaled anesthetics,
lanthanum
Lanthanum is a chemical element with the 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 between lantha ...
, and
riluzole
Riluzole is a medication used to treat amyotrophic lateral sclerosis and other motor neuron diseases. Riluzole delays the onset of ventilator-dependence or tracheostomy in some people and may increase survival by two to three months. Riluzole is ...
.
* Negative allosteric modulators:
flumazenil,
Ro15-4513
Ro15-4513 ''(IUPAC: Ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-1,4-benzodiazepine-3-carboxylate)'' is a weak partial inverse agonist of the benzodiazepine class of drugs, developed by Hoffmann–La Roche in the 1980s. It acts as a invers ...
,
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
Pregnenolone sulfate (PS, PREGS) is an endogenous excitatory neurosteroid that is synthesized from pregnenolone. It is known to have cognitive and memory-enhancing, antidepressant, anxiogenic, and proconvulsant effects.
Biological activity
Pre ...
,
amentoflavone
Amentoflavone is a biflavonoid (''bis''-apigenin coupled at 8 and 3' positions, or 3′,8′′-biapigenin) constituent of a number of plants including ''Ginkgo biloba'', ''Chamaecyparis obtusa'' (hinoki), ''Hypericum perforatum'' (St. ...
, 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 periodi ...
.
* Inverse allosteric agonists:
beta-carbolines (ex.
Harmine,
Harmaline,
Tetrahydroharmine
Tetrahydroharmine (THH) is a fluorescent indole alkaloid that occurs in the tropical liana species ''Banisteriopsis caapi''.
THH, like other harmala alkaloids in ''B. caapi'', namely harmaline and harmine, is a reversible inhibitor of monoamine ...
).
* Second-order modulators:
(−)‐epigallocatechin‐3‐gallate.
* Non-competitive channel blockers:
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, polyyne ...
,
oenanthotoxin
Oenanthotoxin is a toxin extracted from hemlock water-dropwort (''Oenanthe crocata'') and other plants of the genus '' Oenanthe''. It is a central nervous system poison, and acts as a noncompetitive antagonist of the neurotransmitter gamma-aminob ...
,
pentylenetetrazol
Pentylenetetrazol, also known as pentylenetetrazole, leptazol, metrazol, pentetrazol (INN), pentamethylenetetrazol, Corazol, Cardiazol, Deumacard, or PTZ, is a drug formerly used as a circulatory and respiratory stimulant. High doses cause convuls ...
,
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
Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...
,
amnesic
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 o ...
,
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 t ...
,
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
Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep problem ...
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 sometimes used as a s ...
. Some of the subtype-selective negative allosteric modulators such as
α5IA are being investigated for their
nootropic 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
Adipiplon (developmental code name NG2-73) 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.
Adipiplon is ...
. 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
L-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. The compound was developed by Merck, Sharp and Dohme ...
(both partial agonists at some subtypes, but weak antagonists at others)
*
QH-ii-066
QH-II-66 (QH-ii-066) 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 ...
(full agonist highly selective for α
5 subtype)
*
α5IA (selective inverse agonist for α
5 subtype)
*
SL-651,498
SL651498 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. It has similar effects to benzodiazepine drugs, but is ...
(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 anesthetic
An inhalational anesthetic is a chemical compound possessing general anesthetic properties that can be delivered via inhalation. They are administered through a face mask, laryngeal mask airway or tracheal tube connected to an anaesthetic vapori ...
s,
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 f ...
,
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 coin ...
s, and
alcohol
Alcohol most commonly refers to:
* Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom
* Alcohol (drug), an intoxicant found in alcoholic drinks
Alcohol may also refer to:
Chemicals
* Ethanol, one of sev ...
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 "o ...
deviations. There are indication that the latter may be triggered by, among other factors,
social stress or
occupational burnout.
See also
*
4-Iodopropofol
4-Iodopropofol is a drug derived from the commonly used sedative anaesthetic agent, propofol. 4-Iodopropofol has similar effects to propofol on isolated receptors, acting primarily as a GABAA positive modulator and sodium channel blocker, but ...
*
GABA receptor
The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory compound in the mature vertebrate central nervous system. There are two classes of GABA receptors: GABAA and ...
*
GABAB receptor
*
GABAA-ρ receptor
*
Gephyrin
*
Glycine receptor
The glycine receptor (abbreviated as GlyR or GLR) is the receptor of the amino acid neurotransmitter glycine. GlyR is an ionotropic receptor that produces its effects through chloride current. It is one of the most widely distributed inhibitory ...
*
GABAA receptor positive allosteric modulators
*
GABAA receptor negative allosteric modulators
References
Further reading
*
*
*
*
External links
*
{{DEFAULTSORT:Gabaa Receptor
Transmembrane receptors
Ion channels
GABA