The glycine receptor (abbreviated as GlyR or GLR) is the
receptor
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
of the
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
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.
Neu ...
glycine. GlyR is an
ionotropic receptor that produces its effects through
chloride current. It is one of the most widely distributed inhibitory receptors 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 ...
and has important roles in a variety of physiological processes, especially in mediating inhibitory neurotransmission in the
spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the sp ...
and
brainstem.
The receptor can be activated by a range of simple
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
s including glycine,
β-alanine and
taurine, and can be selectively blocked by the high-affinity competitive antagonist
strychnine
Strychnine (, , US chiefly ) is a highly toxic, colorless, bitter, crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine, when inhaled, swallowed, or absorbed through the e ...
.
Caffeine
Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class. It is mainly recreational drug use, used recreationally as a Nootropic, cognitive enhancer, increasing alertness and attentional perfor ...
is a competitive antagonist of GlyR.
Gephyrin has been shown to be necessary for GlyR clustering at inhibitory synapses.
GlyR is known to colocalize with the
GABAA receptor on some
hippocampal neurons.
Nevertheless, some exceptions can occur in the central nervous system where the GlyR α1 subunit and gephyrin, its anchoring protein, are not found in
dorsal root ganglion neurons despite the presence of
GABAA receptors.
History
Glycine and its receptor were first suggested to play a role in inhibition of cells in 1965. Two years later, experiments showed that glycine had a hyperpolarizing effect on spinal motor neurons due to increased chloride conductance through the receptor. Then, in 1971, glycine was found to be localized in the spinal cord using autoradiography. All of these discoveries resulted in the conclusion that glycine is a primary inhibitory neurotransmitter of the spinal cord that works via its receptor.
Arrangement of subunits
Strychnine-sensitive GlyRs are members of a family of
ligand-gated ion channels. Receptors of this family are arranged as five
subunit
Subunit may refer to:
* Subunit HIV vaccine, a class of HIV vaccine
*Protein subunit, a protein molecule that assembles with other protein molecules
*Monomer, a molecule that may bind chemically to other molecules to form a polymer
* Sub-subunit, ...
s surrounding a central pore, with each subunit composed of four
α helical transmembrane segments.
There are presently four known isoforms of 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 elect ...
-binding α-subunit (α
1-4) of GlyR (
GLRA1
Glycine receptor subunit alpha-1 is a protein that in humans is encoded by the ''GLRA1'' gene.
Function
The inhibitory glycine receptor mediates postsynaptic inhibition in the spinal cord and other regions of the central nervous system. It is ...
,
GLRA2
Glycine receptor subunit alpha-2 is a protein that in humans is encoded by the ''GLRA2'' gene.
See also
* Glycine receptor
The glycine receptor (abbreviated as GlyR or GLR) is the receptor of the amino acid neurotransmitter glycine. GlyR i ...
,
GLRA3
The Glycine receptor subunit alpha-3 is a protein that in humans is encoded by the ''GLRA3'' gene. The protein encoded by this gene is a subunit of the glycine receptor
The glycine receptor (abbreviated as GlyR or GLR) is the receptor of t ...
,
GLRA4
The glycine receptor, alpha 4, also known as GLRA4, is a human pseudogene. The protein encoded by this gene is a subunit of the glycine receptor
The glycine receptor (abbreviated as GlyR or GLR) is the receptor of the amino acid neurotransm ...
) and a single β-subunit (
GLRB
Glycine receptor subunit beta is a protein that in humans is encoded by the ''GLRB'' gene.
The inhibitory glycine receptor mediates postsynaptic inhibition in the spinal cord and other regions of the central nervous system. It is a pentameric r ...
). The adult form of the GlyR is the heteromeric α
1β receptor, which is believed to have a stoichiometry (proportion) of three α
1 subunits and two β subunits
or four α
1 subunits and one β subunit.
The embryo form on the other hand, is made up of five α2 subunits.
The α-subunits are also able to form functional homo
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 microbiol ...
s in
heterologous expression systems in
African clawed frog oocyte
An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The female ...
s or mammalian
cell lines, which are useful for studies of channel
pharmacokinetics
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
and
pharmacodynamics
Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms ...
.
The β subunit is unable to form functional channels without α subunits but determines the synaptic localization of GlyRs and the pharmacological profile of glycinergic currents.
Function
Adults
In mature adults,
glycine is a inhibitory neurotransmitter found in the spinal cord and regions of the brain.
As it binds to a glycine receptor, a conformational change is induced, and the channel created by the receptor opens. As the channel opens, chloride ions are able to flow into the cell which results in
hyperpolarization. In addition to this hyperpolarization which decreases the likelihood of action potential propagation, glycine is also responsible for decreasing the transmission of both inhibitory and excitatory neurotransmitters as it binds to its receptor.
This is called the "shunting" effect and can be explained by
Ohm's Law. As the receptor is activated, the membrane conductance is increased and the membrane resistance is decreased. According to Ohm's Law, as resistance decreases, so does voltage. A decreased postsynaptic voltage results in a decreased transmission of neurotransmitters.
Embryos
In developing embryos, glycine has the opposite effect as it does in adults. It is an excitatory neurotransmitter.
This is due to the fact that chloride has a more positive equilibrium potential in early stages of life due to the high expression of
NKCC1. This moves one sodium, one potassium and two chloride ions into the cell, resulting in a higher intracellular chloride concentration. When glycine binds to its receptor, the result is an efflux of chloride, instead of an influx as it happens in mature adults. The efflux of chloride causes the membrane potential to become more positive, or depolarized. As the cells mature, the K+-Cl- cotransporter 2 (
KCC2) is expressed, which moves potassium and chloride out of the cell, decreasing the intracellular chloride concentration. This allows the receptor to switch to an inhibitory mechanism as described above for adults.
Glycine receptors in diseases
Disruption of GlyR surface expression or reduced ability of expressed GlyRs to conduct chloride ions results in the rare neurological disorder,
hyperekplexia. The disorder is characterized by an exaggerated response to unexpected stimuli which is followed by a temporary but complete muscular rigidity often resulting in an unprotected fall. Chronic injuries as a result of the falls are symptomatic of the disorder.
A mutation in GLRA1 is responsible for some cases of
stiff person syndrome.
Ligands
Agonists
*
β-Alanine
*
D-Alanine
*
Gelsemine
*
Glycine
*
Hypotaurine
*
Ivermectin
*
L-Alanine
*
L-Proline
*
L-Serine
*
Milacemide
*
Quisqualamine
*
Sarcosine
*
Taurine
*
THC
*
L-Theanine
Positive Allosteric Modulators
*
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 ...
*
Toluene
Toluene (), also known as toluol (), is a substituted aromatic hydrocarbon. It is a colorless, water-insoluble liquid with the smell associated with paint thinners. It is a mono-substituted benzene derivative, consisting of a methyl group (CH3) ...
Antagonists
*
Bicuculline
*
Brucine
Brucine, is an alkaloid closely related to strychnine, most commonly found in the ''Strychnos nux-vomica'' tree. Brucine poisoning is rare, since it is usually ingested with strychnine, and strychnine is more toxic than brucine. In synthetic che ...
*
Caffeine
Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class. It is mainly recreational drug use, used recreationally as a Nootropic, cognitive enhancer, increasing alertness and attentional perfor ...
*
Levorphanol
Levorphanol (brand name Levo-Dromoran) is an opioid medication used to treat moderate to severe pain. It is the levorotatory enantiomer of the compound racemorphan. Its dextrorotatory counterpart is dextrorphan.
It was first described in Germa ...
*
Picrotoxin
*
Strychnine
Strychnine (, , US chiefly ) is a highly toxic, colorless, bitter, crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine, when inhaled, swallowed, or absorbed through the e ...
*
Tutin
*
Quercetin
References
External links
*
{{Glycinergics
Ionotropic receptors
Cell signaling