Glutamate receptor
Encyclopedia
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
al cells. Glutamate is one of the 20 amino acids used to assemble proteins and as a result is abundant in many areas of the body, but it also functions as a 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...
and is particularly abundant in the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
. Glutamate receptors are responsible for the glutamate-mediated post-synaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation. Furthermore, glutamate receptors are implicated in the pathologies of a number of neurodegenerative diseases due to their central role in excitotoxicity
Excitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
and their prevalence throughout the central nervous system.
Function
Glutamate is the most prominent neurotransmitter in the body, being present in over 50% of nervous tissue. Glutamate was initially discovered to be a neurotransmitterNeurotransmitter
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...
in insect studies in the early 1960s. The two primary glutamate receptors are named after agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
s that bind to them with high specificity: AMPA
AMPA
AMPA is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate....
(α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) and NMDA
NMDA
N-Methyl-D-aspartic acid or N-Methyl-D-aspartate is an amino acid derivative which acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor...
(N-Methyl-D-Aspartate). One of the major functions of glutamate receptors appears to be the modulation of synaptic plasticity, a property of the brain thought to be vital for memory and learning. Both metabotropic and ionotropic glutamate receptors have been shown to have an effect on synaptic plasticity
Synaptic plasticity
In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...
. An increase or decrease in the number of ionotropic glutamate receptor
Ionotropic glutamate receptor
The ability of synapses to modify their synaptic strength in response to activity is a fundamental property of the nervous system and may be an essential component of learning and memory. There are three classes of ionotropic glutamate receptor, namely NMDA , AMPA and kainate receptors...
s on a post-synaptic cell may lead to long-term potentiation or long-term depression of that cell, respectively. Additionally, metabotropic glutamate receptors may modulate synaptic plasticity by regulating post-synaptic protein synthesis through second messenger systems. Research shows that glutamate receptors are present in CNS glial cells as well as neurons. It is suggested that these glutamate receptors play a role in modulating gene expression in glial cells, both during the proliferation and differentiation of glial precursor cells in brain development and in mature glial cells.
Types
Glutamate receptors can be divided into two groups according to the mechanism by which their activation gives rise to a postsynaptic current. IonotropicLigand-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...
glutamate receptors (iGluRs) form the ion channel pore that activates when glutamate binds to the receptor. Metabotropic
Metabotropic receptor
Metabotropic receptor is a subtype of membrane receptors at the surface or in vesicles of eukaryotic cells.In the nervous system, based on their structural and functional characteristics, neurotransmitter receptors can be classified into two broad categories: metabotropic and ionotropic receptors...
glutamate receptors (mGluRs) indirectly activate ion-channels on the plasma membrane through a signaling cascade that involves G protein
G protein
G proteins are a family of proteins involved in transmitting chemical signals outside the cell, and causing changes inside the cell. They communicate signals from many hormones, neurotransmitters, and other signaling factors. G protein-coupled receptors are transmembrane receptors...
s.
Ionotropic receptors tend to be quicker in relaying information but metabotropic are associated with a more prolonged stimulus. This is due to the usage of many different messengers to carry out the signal but since there is a cascade, just one activation of a G-protein can lead to multiple activations. Glutamate receptors are usually not specifically geared towards glutamate exclusively as the ligand and sometimes even requires another agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
.
There are many specific subtypes of glutamate receptors, and it is customary to refer to primary subtypes by a chemical which binds to it more selectively than glutamate. The research, though, is ongoing as subtypes are identified and chemical affinities measured. There are several compounds which are routinely used in glutamate receptor research and associated with receptor subtypes:
| Type | Name | Agonist(s) >- | rowspan="3" align="center" | ionotropic |
NMDA receptor NMDA receptor The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function.... |
>- | >- | AMPA AMPA AMPA is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate.... >- | align="center" | metabotropic |
mGluR Metabotropic glutamate receptor The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs... |
L-AP4 L-AP4 L-AP4 is a drug used in scientific research, which acts as a group-selective agonist for the group III metabotropic glutamate receptors . It was the first ligand found to act as an agonist selective for this group of mGlu receptors, but does not show selectivity between the different mGluR Group... , ACPD ACPD 1-Amino-1,3-dicarboxycyclopentane is a chemical compound that binds to the metabotropic glutamate receptor , acting as a mGluR agonist. ACPD is a rigid analogue of the neurotransmitter glutamate and does not activate ionotropic glutamate receptors. ACPD can induce convulsions in neonatal rats.... , L-QA Quisqualic acid Quisqualic acid is an agonist for both AMPA receptors and group I metabotropic glutamate receptors. It causes excitotoxicity and is used in neuroscience to selectively destroy neurons in the brain or spinal cord... |
Due to the diversity of glutamate receptors, their subunits are encoded by numerous gene families. Sequence similarities between mammals show a common evolutionary origin for many mGluR and all iGluR genes. There is complete conservation of reading frames and splice sites of GluR genes between chimpanzees and humans, suggesting no gross structural changes after humans diverged from the human-chimpanzee common ancestor. However, there is a possibility that two human-specific "fixed" amino acid substitutions, D71G in GRIN3A and R727H in GRIN3B, are specifically associated with human brain function.
Ionotropic
Ionotropic glutamate receptor subunits and their genes:| Receptor Family | Subunit | Gene | Chromosome (human) |
|---|---|---|---|
| AMPA AMPA receptor The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system . Its name is derived from its ability to be activated by the artificial glutamate analog AMPA... |
GluR1 | GRIA1 GRIA1 Glutamate receptor 1 is a protein that in humans is encoded by the GRIA1 gene.Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes... |
5q33 |
| GluR2 | GRIA2 GRIA2 Glutamate receptor 2 is a protein that in humans is encoded by the GRIA2 gene.- Function :Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes... |
4q32-33 | |
| GluR3 | GRIA3 GRIA3 Glutamate receptor 3 is a protein that in humans is encoded by the GRIA3 gene.- Function :Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes... |
Xq25-26 | |
| GluR4 | GRIA4 GRIA4 Glutamate receptor 4 is a protein that in humans is encoded by the GRIA4 gene.-Interactions:GRIA4 has been shown to interact with CACNG2, GRIP1, PICK1 and PRKCG.-RNA editing:... |
11q22-23 | |
| Kainate Kainate receptor Kainate receptors, or KARs, are non-NMDA ionotropic receptors which respond to the neurotransmitter glutamate. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a drug first isolated from red algae Digenea simplex. KARs are less well... |
GluR5 | GRIK1 GRIK1 Glutamate receptor, ionotropic, kainate 1, also known as GRIK1, is a protein that in humans is encoded by the GRIK1 gene.- Function :... |
21q21.1-22.1 |
| GluR6 | GRIK2 GRIK2 Glutamate receptor, ionotropic kainate 2 is a protein that in humans is encoded by the GRIK2 gene.- Clinical significance :Homozygosity for a GRIK2 deletion-inversion mutation is associated with nonsyndromic autosomal recessive mental retardation.... |
6q16.3-q21 | |
| GluR7 | GRIK3 GRIK3 Glutamate receptor, ionotropic kainate 3 is a protein that in humans is encoded by the GRIK3 gene.... |
1p34-p33 | |
| KA-1 | GRIK4 GRIK4 GRIK4 is a kainate receptor subtype belonging to the family of ligand-gated ion channels which is encoded by the gene.-Function:... |
11q22.3 | |
| KA-2 | GRIK5 GRIK5 Glutamate receptor, ionotropic kainate 5 is a protein that in humans is encoded by the GRIK5 gene.-Interactions:GRIK5 has been shown to interact with DLG4 and GRIK2.... |
19q13.2 | |
| NMDA NMDA receptor The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function.... |
NR1 | GRIN1 GRIN1 Glutamate [NMDA] receptor subunit zeta-1 is a protein that in humans is encoded by the GRIN1 gene.-Further reading:... |
9q34.3 |
| NR2A | GRIN2A GRIN2A Glutamate [NMDA] receptor subunit epsilon-1 is a protein that in humans is encoded by the GRIN2A gene.-Interactions:GRIN2A has been shown to interact with FYN, DLG4, DLG3, DLG1, Src, PTK2B and Interleukin 16.-Further reading:... |
16p13.2 | |
| NR2B | GRIN2B GRIN2B Glutamate [NMDA] receptor subunit epsilon-2 also known as N-methyl D-aspartate receptor subtype 2B is a protein that in humans is encoded by the GRIN2B gene.- Function :... |
12p12 | |
| NR2C | GRIN2C GRIN2C Glutamate [NMDA] receptor subunit epsilon-3 is a protein that in humans is encoded by the GRIN2C gene.-Interactions:GRIN2C has been shown to interact with DLG4 and DLG3.... |
17q24-q25 | |
| NR2D | GRIN2D GRIN2D Glutamate [NMDA] receptor subunit epsilon-4 is a protein that in humans is encoded by the GRIN2D gene.-Interactions:GRIN2D has been shown to interact with Interleukin 16.... |
19q13.1qter | |
| NR3A | GRIN3A GRIN3A Glutamate [NMDA] receptor subunit 3A is a protein that in humans is encoded by the GRIN3A gene.... |
9q31.1 | |
| NR3B | GRIN3B GRIN3B Glutamate [NMDA] receptor subunit 3B is a protein that in humans is encoded by the GRIN3B gene.... |
19p13.3 |
Metabotropic
Metabotropic glutamate receptors are all named mGluR# and are further broken down into three groups:| Group | Receptor | Gene | Chromosome (human) |
Effect |
|---|---|---|---|---|
| 1 | mGluR1 | GRM1 Metabotropic glutamate receptor 1 The glutamate receptor, metabotropic 1, also known as GRM1, is a human gene which encodes the metabotropic glutamate receptor 1 protein.-Function:... |
6q24 | Increase in Ca2+ concentration in the cytoplasm. |
| mGluR5 | GRM5 Metabotropic glutamate receptor 5 Metabotropic glutamate receptor 5 is a protein that in humans is encoded by the GRM5 gene.- Function :The amino acid L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors... |
11q14.3 | Release of K+ from the cell by activating K+ ionic channels | |
| 2 | mGluR2 | GRM2 Metabotropic glutamate receptor 2 Metabotropic glutamate receptor 2 is a protein that in humans is encoded by the GRM2 gene.-PAMs:The development of subtype-2-selective positive allosteric modulators experienced steady advance in recent years... |
3p21.2 | Inhibition of adenylyl cyclase causing shutdown of the cAMP-dependent pathway And therefore decreasing amount of cAMP Cyclic adenosine monophosphate Cyclic adenosine monophosphate is a second messenger important in many biological processes... |
| mGluR3 | GRM3 | 7q21.1-q21.2 | ||
| 3 | mGluR4 | GRM4 Metabotropic glutamate receptor 4 Metabotropic glutamate receptor 4 is a protein that in humans is encoded by the GRM4 gene.Together with GRM6, GRM7 and GRM8 it belongs to group III of the metabotropic glutamate receptor family. Group III receptors are linked to the inhibition of the cyclic AMP cascade.Activation of GRM4 has... |
6p21.3 | Activation of Ca2+ channels, allowing more Ca2+ to enter the cell |
| mGluR6 | GRM6 Metabotropic glutamate receptor 6 Glutamate receptor, metabotropic 6, also known as GRM6, is a protein which in humans is encoded by the GRM6 gene.- Function :L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors... |
5q35 | ||
| mGluR7 | GRM7 Metabotropic glutamate receptor 7 Metabotropic glutamate receptor 7 is a protein that in humans is encoded by the GRM7 gene.-Agonists:*AMN082: allosteric agonist; induces rapid internalization; non-glutamatergic binding component-Interactions:... |
3p26-p25 | ||
| mGluR8 | GRM8 Metabotropic glutamate receptor 8 Metabotropic glutamate receptor 8 is a protein that in humans is encoded by the GRM8 gene.-Further reading:... |
7q31.3-q32.1 |
Structure and mechanism
Glutamate receptors exist primarily in the central nervous systemCentral 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...
. These receptors can be found on the dendrites of post-synaptic cells and bind to glutamate released into the synaptic cleft by pre-synaptic cells. They are also present on both astrocytes and oligodendrocytes. The glutamate binds to the extracellular portion of the receptor and provokes a response, however the various types of receptors can produce different responses. Ionotropic and metabatropic glutamate receptors, with the exception of NMDA, are found on cultured glial cells which can open in response to glutamate and cause cells to activate second messengers to regulate gene expression and release neuroactive compounds. Furthermore, brain slices show glutamate receptors are ubiquitously expressed in both developing and astrocytes and oligodendrocytes in vivo. Because of this, glial glutamate receptors are thought to be vital for glial cell development.
Ionotropic
All ionotropic glutamate receptors in vertebrates are ligand-gated nonselective cation channels which allow the flow of K+, Na+ and sometimes Ca2+ in response to glutamate binding. (In C. elegansCaenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
and Drosophila
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
, invertebrate-specific subunits enable the flow of negative chloride
Chloride
The chloride ion is formed when the element chlorine, a halogen, picks up one electron to form an anion Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. The chloride ion, and its salts such as sodium chloride, are very soluble in water...
ions rather than cations.) Upon binding, the agonist will stimulate direct action of the central pore of the receptor, an ion channel, allowing ion flow and causing EPSC (exitatory post-synaptic current). This current is depolarizing and, if enough glutamate receptors are activated, may trigger an action potential in the post-synaptic neuron. All produce excitatory post-synaptic current, but the speed and duration of the current is different for each type. NMDA receptors have an internal binding site for an Mg2+ ion creating a voltage dependant block which is removed by outward flow of positive current. Since the block must be removed by outward current flow, NMDA receptors rely on the EPSC produced by AMPA receptors to open. NMDA receptors are permeable to Ca2+ which is an important cation in the nervous system and has been linked to gene regulation. It is thought that the flow of Ca2+ through NMDA receptors can cause both LTP and LTD by transducing signaling cascades and regulating gene expression.
Metabotropic
Metabotropic glutamate receptors, which belong to subfamily CClass C GPCR
The class C G-protein-coupled receptors are a class of G-protein coupled receptors that include the metabotropic glutamate receptors and several additional receptors....
of 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 are divided into three groups, with a total of eight sub-types. The mGluRs are composed of three distinct regions: the extracellular region, the transmembrane region, and the intracellular region. The extracellular region is composed of a Venus Flytrap (or VFT) module that binds glutamate, and a cysteine-rich domain that is thought to play a role in transmitting the conformational change induced by ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
binding from in the VFT module to the transmembrane region. The transmembrane region consists of seven transmembrane domains and connects the extracellular region to the intracellular region where G protein coupling occurs. Glutamate binding to the extracellular region of an mGluR causes G proteins bound to the intracellular region to be phosphorylated, affecting multiple biochemical pathways and ion channels in the cell. Because of this, mGluRs can both increase or decrease the exitability of the post synaptic cell, thereby causing a wide range of physiological effects.
Effects outside the central nervous system
Glutamate receptors are thought to be responsible for the reception and transduction of umamiUmami
Umami , popularly referred to as savoriness, is one of the five basic tastes together with sweet, sour, bitter, and salty.-Etymology:Umami is a loanword from the Japanese meaning "pleasant savory taste". This particular writing was chosen by Professor Kikunae Ikeda from umai "delicious" and mi ...
taste stimuli. Taste receptors of the T1R family, belonging to the same class of GPCR as metabotropic Glutamate Receptors are involved. Additionally, the mGluRs as well as ionotropic glutamate receptors in neural cells have been found in taste buds and may contribute to the umami taste. Numerous ionotropic glutamate receptor subunits are expressed by heart tissue, but their specific function is still unknown. Western blot
Western blot
The western blot is a widely used analytical technique used to detect specific proteins in the given sample of tissue homogenate or extract. It uses gel electrophoresis to separate native proteins by 3-D structure or denatured proteins by the length of the polypeptide...
s and northern blot
Northern blot
The northern blot is a technique used in molecular biology research to study gene expression by detection of RNA in a sample. With northern blotting it is possible to observe cellular control over structure and function by determining the particular gene expression levels during differentiation,...
s confirmed the presence of iGluRs in cardiac tissue. Immunohistochemistry localized the iGluRs to cardiac nerve terminals, ganglia, conducting fibers, and some myocardiocytes. Glutamate receptors are (as mentioned above) also expressed in pancreatic islet cells. AMPA iGluRs modulate the secretion of insulin and glucagon in the pancreas, opening the possibility of treatment of diabetes via glutamate receptor antagonists. Small unmyelinated sensory nerve terminals in the skin also express NMDA and non-NMDA receptors. Subcutaneous injections of receptor blockers in rats successfully analgesized skin from formalin-induced inflammation, raising possibilities of targeting peripheral glutamate receptors in the skin for pain treatment.
Clinical significance
So far, no genetic diseases in humans have been linked to mutations of any of the glutamate receptor subunit genes. However, a specific genotype of human GluR6 was discovered to have a slight influence on the age of onset of Huntington's disease. Antibodies to glutamate receptor subunit genes accompany various neurological disorders (e.g. GluR3 in Rasmussen's encephalitisRasmussen's encephalitis
Rasmussen's encephalitis, also known as chronic focal encephalitis , is a rare inflammatory neurological disorder, characterized by frequent and severe seizures, loss of motor skills and speech, hemiparesis , encephalitis , and dementia...
and GluR2 in nonfamilial olivopontocerebellar degeneration, but the exact role of antibodies in disease manifestation is still not entirely known.
Excitotoxicity
Overstimulation of glutamate receptors causes neurodegenerationNeurodegeneration
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...
and neuronal damage through a process called excitotoxicity
Excitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
. Excessive glutamate, or excitotoxins acting on the same glutamate receptors, overactivate glutamate receptors (specifically NMDARs), causing high levels of calcium ions (Ca2+) to influx into the postsynaptic cell.
High Ca2+ concentrations activate a cascade of cell degradation processes involving proteases, lipases, nitric oxide synthase, and a number of enzymes that damage cell structures often to the point of cell death. Ingestion or exposure to excitotoxins that act on glutamate receptors can induce excitotoxicity and cause toxic effects on the 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...
. This becomes a problem for cells as it feeds into a cycle of positive feedback cell death.
Glutamate excitotoxicity triggered by oversitmulation of glutamate receptors also contributes to intracellular oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
. Proximal glial cells use a cystine/glutamate antiporter (xCT) to transport cystine into the cell and glutamate out. Excessive extracellular glutamate concentrations reverse xCT and glial cells no longer have enough cystine to synthesize glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
(GSH), an antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
. Lack of GSH leads to more reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
(ROS) that damages and kills the glial cell, which then cannot reuptake and process extracellular glutamate. This is another positive feedback in glutamate excitotoxicity. In addition, increased Ca2+ concentrations activates nitric oxide synthase
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...
(NOS) and the over-synthesis of nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
(NO). High NO concentration damages mitochondria, leading to more energy depletion, and adds oxidative stress to the neuron as NO is a ROS.
Neurodegeneration
In the case of traumatic brain injuryTraumatic brain injury
Traumatic brain injury , also known as intracranial injury, occurs when an external force traumatically injures the brain. TBI can be classified based on severity, mechanism , or other features...
or cerebral ischemia
Cerebral ischemia
Brain ischemia, also known as cerebral ischemia, is a condition in which there is insufficient blood flow to the brain to meet metabolic demand. This leads to poor oxygen supply or cerebral hypoxia and thus to the death of brain tissue or cerebral infarction / ischemic stroke...
(e.g. cerebral infarction
Infarction
In medicine, infarction refers to tissue death that is caused by a local lack of oxygen due to obstruction of the tissue's blood supply. The resulting lesion is referred to as an infarct.-Causes:...
or hemorrhage), acute neurodegeneration caused by excitotoxicity may spread to proximal neurons through two processes. Hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
and hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
trigger bioenergetic failure; mitochondria stop producing ATP energy. Na+/K+-ATPase
Na+/K+-ATPase
Na+/K+-ATPase is an enzyme located in the plasma membrane in all animals.- Sodium-potassium pumps :Active transport is responsible for cells containing relatively high...
can no longer maintain sodium/potassium ion concentration gradients across the plasma membrane. Glutamate transporters (EAATs), which use the Na+/K+ gradient, reverse glutamate transport (efflux) in affected neurons and astrocytes, and depolarization increases downstream synaptic release of glutamate. In addition, cell death via lysis or apoptosis releases cytoplasmic glutamate outside of the ruptured cell. These two forms of glutamate release cause a continual domino effect of excitotoxic cell death and further increased extracellular glutamate concentrations.
Neurodegenerative diseases
Glutamate receptors’ significance in excitotoxicity links it to many neurogenerative diseases. Conditions such as exposure to excitotoxins, old age, congenital predisposition, and brain trauma can trigger glutamate receptor activation and ensuing excitotoxic neurodegeneration. This damage to the central nervous system propagates symptoms associated with a number of diseases.Neurogenerative diseases thought to be mediated (at least in part) through stimulation of glutamate receptors:
- AIDS dementia complexAIDS dementia complexAIDS dementia complex is a common neurological disorder associated with HIV infection and AIDS. It is a metabolic encephalopathy induced by HIV infection and fueled by immune activation of brain macrophages and microglia...
- Alzheimer’s disease
- amyotrophic lateral sclerosisAmyotrophic lateral sclerosisAmyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
- combined systems disease (vitamin B12 deficiency)
- depression/anxietyAnxietyAnxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
- drug addiction, tolerance, and dependency
- glaucomaGlaucomaGlaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
- hepatic encephalopathyHepatic encephalopathyHepatic encephalopathy is the occurrence of confusion, altered level of consciousness and coma as a result of liver failure. In the advanced stages it is called hepatic coma or coma hepaticum...
- Huntington’s disease
- hydroxybutyric aminoaciduria
- hyperhomocysteinemiaHyperhomocysteinemiaHyperhomocysteinemia or hyperhomocysteinaemia is a medical condition characterized by an abnormally large level of homocysteine in the blood....
and homocysteinuria - hyperprolinemiaHyperprolinemiaHyperprolinemia, also referred to as prolinemia or prolinuria, is a condition which occurs when the amino acid proline is not broken down properly by the enzymes proline oxidase or pyrroline-5-carboxylate dehydrogense, causing a build up of proline in the body.-Hyperprolinemia type I:It is...
- lead encephalopathy
- Leber’s disease
- MELAS syndrome
- MERRF
- mitochondrial abnormalities (and other inherited or acquired biochemical disorders)
- multiple sclerosisMultiple sclerosisMultiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
- neuropathic pain syndromes (e.g. causalgia or painful peripheral neuropathies)
- nonketotic hyperglycinemia
- olivopontocerebellar atrophyOlivopontocerebellar atrophyOlivopontocerebellar atrophy is a term used to define neuronal degeneration in the cerebellum, pontine nuclei, and inferior olivary nucleus...
(some recessive forms) - ParkinsonismParkinsonismParkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The underlying causes of parkinsonism are numerous, and diagnosis can be complex...
- Essential tremorEssential tremorEssential tremor is a slowly progressive neurological disorder whose most recognizable feature is a tremor of the arms that is apparent during voluntary movements such as eating and writing...
- Rett syndromeRett syndromeRett syndrome is a neurodevelopmental disorder of the grey matter of the brain that almost exclusively affects females. The clinical features include small hands and feet and a deceleration of the rate of head growth . Repetitive hand movements, such as wringing and/or repeatedly putting hands into...
- schizophreniaSchizophreniaSchizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
- sulfite oxidase deficiency
- Wernicke’s encephalopath
Potential therapeutic applications
Glutamate receptors have been found to have an influence in ischemiaIschemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
/stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, seizures, Parkinson's Disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, Huntington's Disease
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
, and aching
Ache
Ache may refer to:* Ache, a chronic, painful sensation* Ache , a You've Got Foetus on Your Breath album* "Ache" , a song by No Doubt* Ache Records, a Vancouver-based record label* The American College of Healthcare Executives...
. Almost every disease involving glutamate receptors have very similar if not identical pathways, differing slightly only in the area in the brain where the issue occurs. The following explores some of the treatments currently being proposed by targeting the glutamate receptor pathway.
Ischemia
It has been observed that during ischemia, the brain has an unnaturally high concentration of extracellular glutamate. This is linked to an inadequate supply of ATP which drives the glutamate transport levels that keep the concentrations of glutamate in balance. This usually leads to an excessive activation of glutamate receptors, which may lead to neuronal injury. After this overexposure, the post synaptic terminals tend to keep glutamate around for long periods of time which results in a difficulty in depolarization. AntagonistsReceptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
for NMDA and AMPA receptors seem to have a large benefit, with more aid the sooner it is administered after onset of the neural ischemia.
Seizures
Glutamate receptors have been discovered to have a role in the onset of epilepsyEpilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
. NMDA and metabotropic types have been found to induce epileptic convulsions. Using rodent models
Animal testing on rodents
Rodents are commonly used in animal testing, particularly guinea pigs, hamsters, gerbils, rats, and mice.-The statistics:In the UK in 2004, 1,910,110 mice, 464,727 rats and 37,475 other rodents were used...
, labs have found that the introduction of antagonists to these glutamate receptors help counteract the epileptic symptoms. Since glutamate is a ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
for ligand-gated ion channels, the binding of this neurotransmitter will open gates and increase sodium and calcium conductance. These ions play an integral part in the causes of seizures. Group 1 metabotropic glutamate receptors (mGlu1 and mGlu5) are the primary cause of seizing so applying an antagonist to these receptors helps in preventing convulsions.
Parkinson's disease
Late onset neurological disorders like Parkinson's disease may be partially due to endogenous glutamate binding NMDA and AMPA glutamate receptors. Invitro spinal cord cultures with glutamate transport inhibitors led to degeneration of motor neurons which was counteracted by some AMPA receptor antagonists like GYKI 52466. Research also suggests that the metabotropic glutamate receptor, mGlu4, is directly involved in movement disorders associated with the basal ganglia through selectively modulating glutamate in the striatumStriatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
.
Huntington's disease
In addition to similar mechanisms causing Parkinson's disease in respect to NMDA or AMPA receptors, Huntington's disease was also proposed to exhibit metabolic and mitochondrial deficiency, which exposes striatal neurons to the over activation of NMDA receptors. There has been a proposition of using folic acidFolic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
as a possible treatment for Huntington's due to the inhibition it exhibits on homocysteine
Homocysteine
Homocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...
, which increases vulnerability of nerve cells to glutamate. This could decrease the effect that the glutamate has on glutamate receptors and reduce cell response to a safer level, not reaching excitotoxicity
Excitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
.
Aching
HyperalgesiaHyperalgesia
Hyperalgesia is an increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.-Types:...
is directly involved with spinal NMDA receptors. Administered NMDA antagonists in a clinical setting produce significant side effects, although more research is being done in intrathecal
Intrathecal
Intrathecal is an adjective that refers to something introduced into or occurring in the space under the arachnoid membrane of the brain or spinal cord...
administration. Since the spinal NMDA receptors are what links the area of pain to the brain's pain processing center, the thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
, these glutamate receptors are a prime target for treatment. One proposed way to cope with the pain is actually subconsciously through the visualization technique.
Diabetes
Diabetes is a peculiar case because it is influenced by glutamate receptors present outside of the central nervous system, and it also influences glutamate receptors in the central nervous system.Diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
, an endocrine disorder, induces cognitive impairment and defects of long-term potential in the hippocampus, interfering with synaptic plasticity. Defects of long-term potential in the hippocampus are due to abnormal glutamate receptors, specifically the malfunctioning NMDA glutamate receptors during early stages of the disease.
Research is being done to address the possibility of using hyperglycaemia and insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
to regulate these receptors and restore cognitive functions.
Pancreatic islets regulating insulin and glucagon levels also express glutamate receptors. It is possible to treat diabetes via glutamate receptor antagonists, but not much research has been done. The difficulty of modifying peripheral GluR without having detrimental effects on the central nervous system, which is saturated with GluR, may be the cause of this.
Multiple Sclerosis
Inducing experimental autoimmune encephalomyelitisExperimental autoimmune encephalomyelitis
Experimental autoimmune encephalomyelitis, sometimes Experimental Allergic Encephalomyelitis is an animal model of brain inflammation. It is an inflammatory demyelinating disease of the central nervous system...
(EAE) in animal models as a model for MS
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
has targeted some glutamate receptors as a pathway for potential therapeutic applications. This research has found that a group of drugs interact with the NMDA, AMPA, and kainate glutamate receptor to control neurovascular permeability, inflammatory mediator synthesis, and resident glial cell functions including CNS myelination. Oligodendrocyte
Oligodendrocyte
Oligodendrocytes , or oligodendroglia , are a type of brain cell. They are a variety of neuroglia. Their main function is the insulation of axons in the central nervous system of some vertebrates...
s are the cells in the CNS that myelinate axons. The myelination dysfunction in MS is partly due to the excitotoxicity of those cells. By regulating the drugs which interact with those glutamate receptors, it may be possible to regulate glutamate binding, and thereby reducing levels of Ca2+ influx. The experiments showed improved oligodendrocyte survival and remyelination increased. Furthermore, CNS inflammation, apoptosis, and axonal damage were reduced.
Schizophrenia
It has been found that in schizophreniaSchizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
, the expression of the mRNA for the NR2A subunit of the NMDA glutamate receptor is decreased in a subset of inhibitory interneurons in the cerebral cortex. This is suggested by upregulation of GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
, an inhibitory neurotransmitter. In schizophrenia, the expression of the NR2A subunit of NDMA receptors in mRNA was experimentally undetectable in 49-73% in GABA neurons that usually express it. These are mainly in GABA cells expressing the calcium buffering protein parvalbumin
Parvalbumin
Parvalbumin is a calcium-binding albumin protein with low molecular weight .It has three EF hand motifs and is structurally related to calmodulin and troponin C...
(PV) which exhibits fast-spiking firing properties and target the perisomatic (basket cells) and axo-axonic
Chandelier cell
Chandelier neurons or chandelier cells are a subset of GABA-ergic cortical interneurons. They are described as parvalbumin-containing and fast-spiking to distinguish them from other subtypes of GABAergic neurons. The name comes from the specific shape of their axon arbors, with the terminals...
(chandelier cells) compartments of pyramidal neurons
Pyramidal cell
Pyramidal neurons are a type of neuron found in areas of the brain including cerebral cortex, the hippocampus, and in the amygdala. Pyramidal neurons are the primary excitation units of the mammalian prefrontal cortex and the corticospinal tract. Pyramidal neurons were first discovered and...
. The study found that the density of NR2A mRNA-expressing PV neurons was decreased by as much as 50% in subjects with schizophrenia. In addition, density of immunohistochemically
Immunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
labeled glutamatergic terminals with an antibody against the vesicular glutamate transporter vGluT1 also exhibited a reduction that paralleled the reduction in the NR2A-expressing PV neurons. Together these observations suggest that glutamatergic innervation of PV-containing inhibitory neurons appears to be deficient in schizophrenia. Expression of NR2A mRNA has also been found to be altered in the inhibitory neurons that contain another calcium buffer, calbindin, targeting the dendrites of pyramidal neurons and the expression of the mRNA for the GluR5 kainate receptor in GABA neurons has also been found to be changed in organisms with schizophrenia. Current research is looking into glutamate receptor antagonists as potential treatments for schizophrenia. Memantine, a weak nonselective NMDA receptor antagonist, was used as an add-on to clozapine therapy in a clinical trial. Refractory schizophrenia patients showed associated improvements in both negative and positive symptoms, underscoring the potential uses of GluR antagonists as antipsychotics. Furthermore, administration of noncompetitive NMDA receptor antagonists have been tested on rat models. Scientists proposed that specific antagonists can act on GABAergic interneurons, enhancing cortical inhibition and preventing excessive glutamatergic transmission associated with schizophrenia. These and other atypical antipsychotic drugs can be used together to inhibit excessive excitability in pyramidal cells, decreasing the symptoms of schizophrenia.
See also
- anti-glutamate receptor antibodiesAnti-glutamate receptor antibodiesAnti-glutamate receptor antibodies are autoantibodies detected in serum and/or cerebrospinal fluid samples of a variety of disorders such as encephalitis, epilepsy and ataxia...
- excitotoxicityExcitotoxicityExcitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
- N-methyl-D-aspartic acid
- glutamate transporterGlutamate transporterExcitatory amino-acid transporters , formerly known as Glutamate transporters, belong to the family of neurotransmitter transporters. They serve to terminate the excitatory neurotransmitter signal by removal of glutamate from the neuronal synapse into Glia cells.In details, the EAATs are...
- metabotropic glutamate receptorMetabotropic glutamate receptorThe metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs...
- synaptic plasticitySynaptic plasticityIn neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...
- neurodegenerationNeurodegenerationNeurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...