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 ...
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 am ...
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 ...
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
. GlyR 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 ...
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 par ...
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 spi ...
and
brainstem
The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is cont ...
.
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 am ...
s including glycine,
β-alanine and
taurine
Taurine (), or 2-aminoethanesulfonic acid, is an organic compound that is widely distributed in animal tissues. It is a major constituent of bile and can be found in the large intestine, and accounts for up to 0.1% of total human body weight. It ...
, 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 eye ...
.
Caffeine
Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine t ...
is a competitive antagonist of GlyR.
Gephyrin
Gephyrin is a protein that in humans is encoded by the ''GPHN'' gene.
This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subu ...
has been shown to be necessary for GlyR clustering at inhibitory synapses.
GlyR is known to colocalize with the
GABAA receptor on some
hippocampal
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, an ...
neurons
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 ...
.
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
A dorsal root ganglion (or spinal ganglion; also known as a posterior root ganglion) is a cluster of neurons (a ganglion) in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the dorsa ...
neurons
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 ...
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 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 res ...
s. Receptors of this family are arranged as five
subunits surrounding a central pore, with each subunit composed of four
α helical transmembrane
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
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 electr ...
-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
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generat ...
,
GLRA3
The Glycine receptor subunit alpha-3 is a protein that in humans is encoded by the ''GLRA3'' gene. The protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins pe ...
,
GLRA4
The glycine receptor, alpha 4, also known as GLRA4, is a human pseudogene. 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 f ...
) and a single β-subunit (
GLRB
Glycine receptor subunit beta is a protein that in humans is encoded by the ''GLRB'' gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation ...
). 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
The term heterologous has several meanings in biology.
Gene expression
In cell biology and protein biochemistry, heterologous expression means that a protein is experimentally put into a cell that does not normally make (i.e., express) that ...
expression systems in
African clawed frog
The African clawed frog (''Xenopus laevis'', also known as the xenopus, African clawed toad, African claw-toed frog or the ''platanna'') is a species of African aquatic frog of the family Pipidae. Its name is derived from the three short claws ...
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 line
An immortalised cell line is a population of cells from a multicellular organism which would normally not proliferate indefinitely but, due to mutation, have evaded normal cellular senescence and instead can keep undergoing division. The cell ...
s, 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 (fo ...
.
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
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
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
Ohm's law states that the current through a conductor between two points is directly proportional to the voltage across the two points. Introducing the constant of proportionality, the resistance, one arrives at the usual mathematical equat ...
. 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
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 differe ...
. 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
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 ...
) 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
Hyperekplexia (; "exaggerated surprise") is a very rare neurologic disorder classically characterised by pronounced startle responses to tactile or acoustic stimuli and hypertonia. The hypertonia may be predominantly truncal, attenuated during ...
. 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
Stiff-person syndrome (SPS), also known as stiff-man syndrome (SMS), is a rare neurologic disorder of unclear cause characterized by progressive rigidity and stiffness. The stiffness primarily affects the truncal muscles and is superimposed by s ...
.
Ligands
Agonists
*
β-Alanine
*
D-Alanine
*
Gelsemine
Gelsemine (C20H22N2O2) is an indole alkaloid isolated from flowering plants of the genus ''Gelsemium'', a plant native to the subtropical and tropical Americas, and southeast Asia, and is a highly toxic compound that acts as a paralytic, exposu ...
*
Glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
*
Hypotaurine
Hypotaurine is a sulfinic acid that is an intermediate in the biosynthesis of taurine. Like taurine, it also acts as an endogenous neurotransmitter via action on the glycine receptors. It is an osmolyte with antioxidant properties.
Hypotaurine is ...
*
Ivermectin
Ivermectin (, '' EYE-vər-MEK-tin'') is an antiparasitic drug. After its discovery in 1975, its first uses were in veterinary medicine to prevent and treat heartworm and acariasis. Approved for human use in 1987, today it is used to treat inf ...
*
L-Alanine
*
L-Proline
*
L-Serine
*
Milacemide
*
Quisqualamine
Quisqualamine is the α-decarboxylated analogue of quisqualic acid, as well as a relative of the neurotransmitters glutamate and γ-aminobutyric acid (GABA). α-Decarboxylation of excitatory amino acids can produce derivatives with inhibitory ...
*
Sarcosine
Sarcosine, also known as ''N''-methylglycine, or monomethylglycine, is a monopeptide with the formula CH3N(H)CH2CO2H. It exists at neutral pH as the zwitterion CH3N+(H)2CH2CO2−, which can be obtained as a white, water-soluble powder. Like some ...
*
Taurine
Taurine (), or 2-aminoethanesulfonic acid, is an organic compound that is widely distributed in animal tissues. It is a major constituent of bile and can be found in the large intestine, and accounts for up to 0.1% of total human body weight. It ...
*
THC
Tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) describes multiple isomers, the term ''THC' ...
*
L-Theanine
Theanine , also known as L-γ-glutamylethylamide and ''N''5-ethyl-L-glutamine, is an amino acid analogue of the proteinogenic amino acids L-glutamate and L-glutamine and is found primarily in particular plant and fungal species. It was disco ...
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 (chemistry), alcohol with the chemical formula . Its formula can be also written as or (an ethyl ...
*
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) at ...
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 ...
*
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 ch ...
*
Caffeine
Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine t ...
*
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 German ...
*
Picrotoxin
Picrotoxin, also known as cocculin, is a poisonous crystalline plant compound. It was first isolated by the French pharmacist and chemist Pierre François Guillaume Boullay (1777–1869) in 1812. The name "picrotoxin" is a combination of the Gree ...
*
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 eye ...
*
Tutin
Tutin may refer to:
Places
*Tutin, Serbia, town in Serbia
Surname
*Arthur Tutin (1907–1961), English footballer
*Dorothy Tutin (1930–2001), English actress
*Mary Tutin, maiden name of Mary Gillick (1881–1965), English sculptor
*Tom Tutin (1 ...
*
Quercetin
Quercetin is a plant flavonol from the flavonoid group of polyphenols. It is found in many fruits, vegetables, leaves, seeds, and grains; capers, red onions, and kale are common foods containing appreciable amounts of it. It has a bitter flavor a ...
References
External links
*
{{Glycinergics
Ionotropic receptors
Cell signaling