GABA receptor
Encyclopedia
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
that respond to the neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
gamma-aminobutyric acid
Gamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
(GABA), the chief inhibitory neurotransmitter in the vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. There are two classes of GABA receptors: GABAA and GABAB.
GABAA receptors are ligand-gated ion channels (also known as ionotropic receptors), whereas GABAB receptors are G protein-coupled receptors (also known as metabotropic receptors).
Ligand-gated ion channels: GABAA
It has long been recognized that the fast response of neurons to GABA that is blocked by bicucullineBicuculline
Bicuculline is a light-sensitive competitive antagonist of GABAA receptors. It was originally identified in 1932 in plant alkaloid extracts and has been isolated from Dicentra cucullaria, Adlumia fungosa, Fumariaceae, and several Corydalis species. Since it blocks the inhibitory action of GABA...
and picrotoxin
Picrotoxin
Picrotoxin, also known as cocculin, is a poisonous crystalline plant compound, first isolated by Pierre Boullay in 1812. The name "picrotoxin" is a combination of the Greek words "picros" and "toxicon" ....
is due to direct activation of an anion channel. This channel was subsequently termed the GABAA receptor. Fast-responding GABA receptors are members of family of Cys-loop ligand-gated
Ligand-gated ion channel
Ligand-gated ion channels are one type of ionotropic receptor or channel-linked receptor. They are a group of transmembrane ion channels that are opened or closed in response to the binding of a chemical messenger , such as a neurotransmitter.The binding site of endogenous ligands on LGICs...
ion channels. Members of this superfamily, which includes nicotinic acetylcholine receptor
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
s, GABAA receptors, glycine
Glycine receptor
The glycine receptor, or GlyR, is the receptor for the amino acid neurotransmitter glycine. GlyR is an ionotropic receptor that produces its effects through chloride current...
and 5-HT3 receptors, possess a characteristic loop formed by a disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
between two cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
residues.
In ionotropic GABAA receptors, binding of GABA molecules to their binding sites in the extracellular part of receptor triggers opening of a chloride ion-selective pore. The increased chloride conductance
Conductance
Conductance may refer to:* Electrical conductance, the ability for electricity to flow a certain path* Fluid conductance, the ability for fluid to transmit through materials* Thermal conductivity, the ability for temperatures to transmit through materials...
drives the membrane potential
Membrane potential
Membrane potential is the difference in electrical potential between the interior and exterior of a biological cell. All animal cells are surrounded by a plasma membrane composed of a lipid bilayer with a variety of types of proteins embedded in it...
towards the reversal potential of the Cl¯ ion which is about –65 mV
MV
-Science and technology:* Maedi-visna virus or visna virus, a virus causing encephalitis and pneumonitis in sheep and goats* Materialized view, a concept in database management systems...
in neurons, inhibiting the firing of new action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
s.
However, there are numerous reports of excitatory GABAA receptors. This phenomenon is due to increased intracellular concentration of Cl¯ ions either during development of the nervous system or in certain cell populations.
After this period of development, a Chloride pump is upregulated and inserted into the cell membrane, pumping Cl- ions into the extracellular space of the cell. Further openings via GABA binding to the receptor then produce inhibitory responses. Over-excitation of this receptor induces receptor remodeling and the eventual invagination of the GABA receptor. As a result, further GABA binding becomes inhibited and IPSPs are no longer relevant.
GABAA-ρ subclass (formerly GABAC)
A subclass of ionotropic GABA receptors, insensitive to typical allosteric modulatorsAllosteric regulation
In biochemistry, allosteric regulation is the regulation of an enzyme or other protein by binding an effector molecule at the protein's allosteric site . Effectors that enhance the protein's activity are referred to as allosteric activators, whereas those that decrease the protein's activity are...
of GABAA receptor channels such as benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s and barbiturate
Barbiturate
Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, as hypnotics, and as anticonvulsants...
s, was designated GABAС receptor. Native responses of the GABAC receptor type occur in retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
l bipolar or horizontal cells across vertebrate species.
GABAС receptors are exclusively composed of ρ (rho) subunits that are related to GABAA receptor subunits. Although the term "GABAС receptor" is frequently used, GABAС may be viewed as a variant within the GABAA receptor family. Others have argued that the differences between GABAС and GABAA receptors are large enough to justify maintaining the distinction between these two subclasses of GABA receptors. However since GABAС receptors are closely related in sequence, structure, and function to GABAA receptors and since other GABAA receptors besides those containing ρ subunits appear to exhibit GABAС pharmacology, the Nomenclature Committee of the IUPHAR
International Union of Basic and Clinical Pharmacology
The International Union of Basic and Clinical Pharmacology is a voluntary, non-profit association representing the interests of scientists in pharmacology-related fields to facilitate Better Medicines through Global Education and Research around the world.-History:Established in 1959 as a section...
has recommended that the GABAС term no longer be used and these ρ receptors should be designated as the ρ subfamily of the GABAA receptors (GABAA-ρ).
G protein coupled receptor: GABAB
A slow response to GABA is mediated by GABAB receptorsGABA B receptor
GABAB receptors are metabotropic transmembrane receptors for gamma-aminobutyric acid that are linked via G-proteins to potassium channels...
, originally defined on the basis of pharmacological properties.
In studies focused on the control of neurotransmitter release, it was noted that a GABA receptor was responsible for modulating evoked release in a variety of isolated tissue preparations. This ability of GABA to inhibit neurotransmitter release from these preparations was not blocked by bicuculline, was not mimicked by isoguvacine
Isoguvacine
Isoguvacine is a GABAA receptor agonist used in scientific research....
, and was not dependent on Cl¯, all of which are characteristic of the GABAA
GABA A receptor
The GABAA receptor is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid , the major inhibitory neurotransmitter in the central nervous system. Upon activation, the GABAA receptor selectively conducts Cl- through its pore, resulting in...
receptor. The most striking discovery was the finding that baclofen
Baclofen
Baclofen is a derivative of gamma-aminobutyric acid . It is primarily used to treat spasticity and is under investigation for the treatment of alcoholism....
(β-parachlorophenyl GABA), a clinically employed spasmolytic mimicked, in a stereoselective manner, the effect of GABA.
Later ligand-binding studies provided direct evidence of binding sites for baclofen on central neuronal membranes. cDNA cloning confirmed that the GABAB receptor belongs to the family of G-protein coupled receptors. Additional information on GABAB receptors has been reviewed elsewhere.
Summary
Thus, GABAA receptors are ligand-gated ion channelLigand-gated ion channel
Ligand-gated ion channels are one type of ionotropic receptor or channel-linked receptor. They are a group of transmembrane ion channels that are opened or closed in response to the binding of a chemical messenger , such as a neurotransmitter.The binding site of endogenous ligands on LGICs...
s, whereas GABAB receptors are G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
s.
This has a parallel to several other receptors in the body, in which a single molecule binds to receptors which function in completely different ways:
- acetylcholineAcetylcholineThe chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
binds to nicotinic and muscarinic acetylcholine receptors - serotoninSerotoninSerotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
binds to 5-HT35-HT3 receptorThe 5-HT3 receptor is a member of the superfamily of ligand-gated ion channels, a superfamily that also includes the neuronal nicotinic acetylcholine receptors , and the inhibitory neurotransmitter receptors for GABA and glycine...
and metabotropic receptors - glutamate binds to ionotropic and metabotropic receptors
- purinePurineA purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
s bind to ionotropic nucleotide-gated P2X and G protein-coupled P2Y receptors