Glutamate receptor
Glutamate receptors are
Glutamate receptors are implicated in a number of
Function
Glutamate
Glutamate is the most prominent neurotransmitter in the body, and is the main excitatory neurotransmitter, being present in over 50% of nervous tissue.[2][3] Glutamate was initially discovered to be a neurotransmitter in insect studies in the early 1960s.
Glutamate is also used by the brain to synthesize
Glutamate receptors
Mammalian glutamate receptors are classified based on their pharmacology.[5] However, glutamate receptors in other organisms have different pharmacology, and therefore these classifications do not hold. 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.[6] An increase or decrease in the number of ionotropic glutamate receptors on a postsynaptic cell may lead to long-term potentiation or long-term depression of that cell, respectively.[7][8][9] Additionally, metabotropic glutamate receptors may modulate synaptic plasticity by regulating postsynaptic protein synthesis through second messenger systems.[10] Research shows that glutamate receptors are present in CNS glial cells as well as neurons.[11] These glutamate receptors are suggested to 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.[12]
Glutamate receptors serve to facilitate the impact of the neurotransmitter glutamate in the central nervous system. These receptors are pivotal in excitatory synaptic transmission, synaptic plasticity, and neuronal development. They are vital for functions like learning, memory, and neuronal communication.[13] Various subtypes of glutamate receptors, such as NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), and kainate receptors, have distinct roles in synaptic transmission and plasticity.[13][14]
1. NMDA (N-methyl-D-aspartate) receptors: These receptors are involved in synaptic plasticity, learning, and memory. They are unique in that they require both glutamate and the co-agonist glycine to activate, and they are also voltage-dependent, meaning they only open when the postsynaptic membrane is depolarized. NMDA receptors are permeable to calcium ions, which can trigger intracellular signaling pathways that lead to changes in synaptic strength.[14]
2. AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors: These receptors mediate the majority of fast excitatory synaptic transmission in the brain. They are permeable to sodium and potassium ions and are responsible for the rapid depolarization of the postsynaptic membrane that underlies the excitatory postsynaptic potential (EPSP). AMPA receptors are also involved in synaptic plasticity, particularly in the early stages of long-term potentiation (LTP).
3. Kainate receptors: These receptors are involved in both pre- and postsynaptic signaling and are thought to play a role in regulating synaptic transmission and plasticity. They are activated by the neurotransmitter kainate and are permeable to both sodium and potassium ions. Kainate receptors are expressed in a variety of brain regions and are involved in processes such as sensory processing, motor control, and learning and memory.
Each subtype of glutamate receptor has a unique function and plays a crucial role in neuronal communication and plasticity.[14]
Types
Ionotropic glutamate receptors (iGluRs) form the ion channel pore that activates when glutamate binds to the receptor. Metabotropic glutamate receptors (mGluRs) affect the cell through a signal transduction cascade, and they may be primarily activating (mGlur1/5) or primarily inhibitory (mGlur2/3 and mGlur4/6/7/8). Ionotropic receptors tend to be quicker in relaying information, but metabotropic ones are associated with a more prolonged stimulus. The signalling cascade induced by metabotropic receptor activation means that even a relatively brief or small synaptic signal can have large and long-lasting effects, i.e. the system can have high "gain." NMDA receptor activation is particularly complex, as channel opening requires not only glutamate binding but also glycine or serine binding simultaneously at a separate site, and it also displays a degree of voltage dependence due to Zn2+ or Mg2+ binding in the pore.[15] Furthermore, Ca2+ currents through the NMDA receptor modulate not just the membrane potential but act as an important second messenger system. The particular dynamics of the NMDAR allow it to function as a neural coincidence detector, and the NMDAR Ca2+ currents are critical in synaptic plasticity (LTP and LTD) and learning and memory in general.[15]
Of the many specific subtypes of glutamate receptors, it is customary to refer to primary subtypes by a chemical that binds to it more selectively than glutamate. The research, however, is ongoing, as subtypes are identified and chemical affinities measured. Several compounds are routinely used in glutamate receptor research and associated with receptor subtypes:
Type | Name | Agonist(s) | Antagonists |
ionotropic | NMDA receptor | NMDA
|
Ketamine |
Kainate receptor | Kainate
|
UBP-302 | |
AMPA receptor | AMPA | Perampanel | |
Group 1 metabotropic | mGluR1, mGluR5 | DHPG | LY-344,545
|
Group 2 metabotropic | mGluR2, mGluR3 | DCG-IV | LY-341,495
|
Group 3 metabotropic | mGluR4, mGluR6, mGluR7, mGluR8 | L-AP4
|
MMPIP (mGlur7) |
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.[16] Conservation of reading frames and splice sites of GluR genes between chimpanzees and humans is complete, 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.[17]
Ionotropic
Mammalian ionotropic glutamate receptor subunits and their genes:[18][19]
Mammalian receptor family | Subunit
(Old nomenclature) |
Gene | Chromosome (human) |
---|---|---|---|
AMPA | GluA1 (GluR1) | GRIA1 | 5q33 |
GluA2 (GluR2) | GRIA2 | 4q32-33 | |
GluA3 (GluR3) | GRIA3 | Xq25-26 | |
GluA4 (GluR4) | GRIA4 | 11q22-23 | |
Kainate | GluK1 (GluR5) | GRIK1 | 21q21.1-22.1 |
GluK2 (GluR6) | GRIK2 | 6q16.3-q21 | |
GluK3 (GluR7) | GRIK3 | 1p34-p33 | |
GluK4 (KA-1) | GRIK4 | 11q22.3 | |
GluK5 (KA-2) | GRIK5 | 19q13.2 | |
NMDA | GluN1(NR1) | GRIN1 | 9q34.3 |
GluN2A (NR2A) | GRIN2A | 16p13.2 | |
GluN2B (NR2B) | GRIN2B | 12p12 | |
GluN2C (NR2C) | GRIN2C | 17q24-q25 | |
GluN2D (NR2D) | GRIN2D | 19q13.1qter | |
GluN3A (NR3A) | GRIN3A | 9q31.1 | |
GluN3B (NR3B) | GRIN3B | 19p13.3 |
Metabotropic
Mammalian metabotropic glutamate receptors are all named mGluR# and are further broken down into three groups:
Group | Receptor | Gene | Chromosome (human) |
Effect |
---|---|---|---|---|
1 | mGluR1 | GRM1 | 6q24 | Increase in Ca2+ concentration in the cytoplasm. |
mGluR5 | GRM5 | 11q14.3 | Release of K+ from the cell by activating K+ ionic channels | |
2 | mGluR2 | GRM2 | 3p21.2 | Inhibition of adenylyl cyclase causing shutdown of the cAMP-dependent pathway And therefore decreasing amount of cAMP |
mGluR3 | GRM3
|
7q21.1-q21.2 | ||
3 | mGluR4 | GRM4 | 6p21.3 | Activation of Ca2+ channels, allowing more Ca2+ to enter the cell[20] |
mGluR6 | GRM6 | 5q35 | ||
mGluR7 | GRM7 | 3p26-p25 | ||
mGluR8 | GRM8 | 7q31.3-q32.1 |
In other (non mammalian) organisms, the classification and subunit composition of glutamate receptors is different.
Structure, mechanism and function
Glutamate receptors exist primarily in the
Ionotropic
Ionotropic glutamate receptors, by definition, are ligand-gated nonselective
Metabotropic
Metabotropic glutamate receptors, which belong to
Outside the central nervous system
Glutamate receptors are thought to be responsible for the reception and transduction of umami 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.[28] Numerous ionotropic glutamate receptor subunits are expressed by heart tissue, but their specific function is still unknown. Western blots and northern blots confirmed the presence of iGluRs in cardiac tissue. Immunohistochemistry localized the iGluRs to cardiac nerve terminals, ganglia, conducting fibers, and some myocardiocytes.[29] Glutamate receptors are (as mentioned above) also expressed in pancreatic islet cells.[30] AMPA iGluRs modulate the secretion of insulin and glucagon in the pancreas, opening the possibility of treatment of diabetes via glutamate receptor antagonists.[31][32] 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.[33]
General clinical implications
Specific medical conditions and symptoms are discussed below.
Autoimmunity and antibody interactions with glutamate receptors and their subunit genes
Various neurological disorders are accompanied by
Excitotoxicity
Overstimulation of glutamate receptors causes
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.[39] Ingestion of or exposure to excitotoxins that act on glutamate receptors can induce excitotoxicity and cause toxic effects on the central nervous system.[40] This becomes a problem for cells, as it feeds into a cycle of positive feedback cell death.
Glutamate excitotoxicity triggered by overstimulation of glutamate receptors also contributes to intracellular oxidative stress. Proximal glial cells use a cystine/glutamate antiporter (xCT) to transport cystine into the cell and glutamate out. Excessive extracellular glutamate concentrations reverse xCT, so glial cells no longer have enough cystine to synthesize glutathione (GSH), an antioxidant.[41] Lack of GSH leads to more reactive oxygen species (ROSs) that damage and kill the glial cell, which then cannot reuptake and process extracellular glutamate.[42] This is another positive feedback in glutamate excitotoxicity. In addition, increased Ca2+ concentrations activate nitric oxide synthase (NOS) and the over-synthesis of nitric oxide (NO). High NO concentration damages mitochondria, leading to more energy depletion, and adds oxidative stress to the neuron as NO is a ROS.[43]
Neurodegeneration
In the case of
Glutamate receptors' significance in excitotoxicity also 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.[46]
Conditions with demonstrated associations to glutamate receptors
A number of diseases in humans have a proven association with
Excessive synaptic receptor stimulation by glutamate is directly related to many conditions. Magnesium is one of many antagonists at the glutamate receptor, and magnesium deficiencies have demonstrated relationships with many glutamate receptor-related conditions.[47]
Glutamate receptors have been found to have an influence in
In most cases these are areas of ongoing research.
Aching
Attention deficit hyperactivity disorder (ADHD)
In 2006 the glutamate receptor subunit gene
Further mutations to four different
A SciBX article in January 2012 commented that "
Autism
The etiology of autism may include excessive glutamatergic mechanisms. In small studies, memantine has been shown to significantly improve language function and social behavior in children with autism.[57][58] Research is underway on the effects of memantine in adults with autism spectrum disorders.[59]
A link between glutamate receptors and autism was also identified via the structural protein ProSAP1 SHANK2 and potentially ProSAP2 SHANK3. The study authors concluded that the study "illustrates the significant role glutamatergic systems play in autism" and "By comparing the data on ProSAP1/Shank2−/− mutants with ProSAP2/Shank3αβ−/− mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype."[51]
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.
Research is being done to address the possibility of using hyperglycemia and insulin to regulate these receptors and restore cognitive functions. Pancreatic islets regulating insulin and glucagon levels also express glutamate receptors.[30] Treating diabetes via glutamate receptor antagonists is possible, 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.
Huntington's disease
In 2004, a specific genotype of human GluR6 was discovered to have a slight influence on the age of onset of Huntington's disease.[61]
In addition to similar mechanisms causing Parkinson's disease with 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.
Ischemia
During ischemia, the brain has been observed to have an unnaturally high concentration of extracellular glutamate.[63] This is linked to an inadequate supply of ATP, which drives the glutamate transport levels that keep the concentrations of glutamate in balance.[64] This usually leads to an excessive activation of glutamate receptors, which may lead to neuronal injury. After this overexposure, the postsynaptic terminals tend to keep glutamate around for long periods of time, which results in a difficulty in depolarization.[64] Antagonists 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.[65]
Multiple sclerosis
Inducing experimental autoimmune encephalomyelitis in animals as a model for multiple sclerosis(MS) has targeted some glutamate receptors as a pathway for potential therapeutic applications.[66] 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. Oligodendrocytes in the CNS 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, regulating glutamate binding may be possible, and thereby reduce the levels of Ca2+ influx. The experiments showed improved oligodendrocyte survival, and remyelination increased. Furthermore, CNS inflammation, apoptosis, and axonal damage were reduced.[66]
Parkinson's disease (Parkinsonism)
Late onset neurological disorders, such as
Rasmussen's encephalitis
In 1994, GluR3 was shown to act as an
Schizophrenia
In
In addition, density of immunohistochemically 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 glutamatergic innervation of PV-containing inhibitory neurons appears to be deficient in schizophrenia.[68] 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,[69] and the expression of the mRNA for the GluR5 kainate receptor in GABA neurons has also been found to be changed in people with schizophrenia.[70]
Current research is targeting glutamate receptor antagonists as potential treatments for schizophrenia.
Seizures
Glutamate receptors have been discovered to have a role in the onset of epilepsy. NMDA and metabotropic types have been found to induce epileptic convulsions. Using rodent models, labs have found that the introduction of antagonists to these glutamate receptors helps counteract the epileptic symptoms.[73] Since glutamate is a ligand 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.[74]
Other diseases suspected of glutamate receptor link
Neurodegenerative diseases with a suspected excitotoxicity link
Neurodegenerative diseases suspected to have a link mediated (at least in part) through stimulation of glutamate receptors:[38][75]
- AIDS dementia complex
- Alzheimer's disease
- Amyotrophic lateral sclerosis
- Combined systems disease (vitamin B12 deficiency)
- Depression/anxiety
- Drug addiction, tolerance, and dependency
- Essential tremor
- Glaucoma
- Hepatic encephalopathy
- Hydroxybutyric aminoaciduria
- homocysteinuria
- Hyperprolinemia
- Lead encephalopathy
- Leber's disease
- MELAS syndrome
- MERRF
- Mitochondrial abnormalities (and other inherited or acquired biochemical disorders)
- Neuropathic pain syndromes (e.g. causalgia or painful peripheral neuropathies)
- Nonketotic hyperglycinemia
- Olivopontocerebellar atrophy (some recessive forms)
- Rett syndrome
- Sulfite oxidase deficiency
- Wernicke's encephalopathy
See also
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External links
- Glutamate+Receptors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- "Metabotropic Glutamate Receptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2016-03-03. Retrieved 2007-10-25.