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! Type !! Name !! Agonist(s) !! Antagonists
|-
| rowspan="3" align="center" | ionotropic || NMDA receptor || NMDA |Ketamine
|-
| Kainate receptor || Kainate|UBP-302
|-
| AMPA receptor || AMPA|Perampanel
|-
| align="center" | Group 1 metabotropic ||mGluR1, mGluR5||DHPG|LY-344,545|Group 2 metabotropic

Metabotropic glutamate receptor 2>mGluR2, mGluR3|DCG-IV|LY-341,495

|Group 3 metabotropic

Metabotropic glutamate receptor 4>mGluR4, Metabotropic glutamate receptor 6	, Metabotropic glutamate receptor 7>mGluR7, mGluR8	2-amino-4-phosphonobutyrate>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.JOURNAL, Suchanek B, Seeburg PH, Sprengel R, Gene structure of the murine N-methyl D-aspartate receptor subunit NR2C, J. Biol. Chem., 270, 1, 41–4, January 1995, 7814402, 10.1074/jbc.270.1.41, 6758394, free, 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.JOURNAL, Goto H, Watanabe K, Araragi N, Kageyama R, Tanaka K, Kuroki Y, Toyoda A, Hattori M, Sakaki Y, Fujiyama A, Fukumaki Y, Shibata H, The identification and functional implications of human-specific "fixed" amino acid substitutions in the glutamate receptor family, BMC Evol. Biol., 9, 224, 2009, 1, 19737383, 2753569, 10.1186/1471-2148-9-224, free, 2009BMCEE...9..224G,

Ionotropic

Mammalian ionotropic glutamate receptor subunits and their genes:JOURNAL, Dingledine R, Borges K, Bowie D, Traynelis SF, The glutamate receptor ion channels, Pharmacol. Rev., 51, 1, 7–61, March 1999, 10049997, JOURNAL, Andersson O, Stenqvist A, Attersand A, von Euler G, Nucleotide sequence, genomic organization, and chromosomal localization of genes encoding the human NMDA receptor subunits NR3A and NR3B, Genomics, 78, 3, 178–84, December 2001, 11735224, 10.1006/geno.2001.6666, {| class="wikitable"! 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:{| class="wikitable"! Group! Receptor! Gene! Chromosome(human)! Effect

1| mGluR1	Metabotropic glutamate receptor 1>GRM1	6q24| Increase in Ca2+ concentration in the cytoplasm.

| mGluR5

Metabotropic glutamate receptor 5>GRM5	11q14.3| Release of K+ from the cell by activating K+ ionic channels

2| mGluR2	Metabotropic glutamate receptor 2>GRM2	3p21.2	Inhibition of adenylyl cyclase causing shutdown of the cAMP-dependent pathwayAnd therefore decreasing amount of cAMP

| mGluR3| GRM3

7q21.1-q21.2

3| mGluR4	Metabotropic glutamate receptor 4>GRM4	6p21.3	Activation of Ca2+ channels, allowing more Ca2+ to enter the cellCONN PJ, ETAL > TITLE = METABOTROPIC GLUTAMATE RECEPTORS IN THE BASAL GANGLIA MOTOR CIRCUIT	VOLUME = 6	PAGES = 787–98	PMID = 16276355	S2CID = 9473598,

| mGluR6

Metabotropic glutamate receptor 6>GRM6	5q35

| mGluR7

Metabotropic glutamate receptor 7>GRM7	3p26-p25

| mGluR8

Metabotropic glutamate receptor 8>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 central nervous system. These receptors can be found on the dendrites of postsynaptic cells and bind to glutamate released into the synaptic cleft by presynaptic cells. They are also present on both astrocytes and oligodendrocytes. Ionotropic and metabotropic 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 mature astrocytes and oligodendrocytes in vivo. Because of this, glial glutamate receptors are thought to be vital for glial cell development.

Ionotropic

Ionotropic glutamate receptors, by definition, are ligand-gated nonselective cation channels that allow the flow of K+, Na+ and sometimes Ca2+ in response to glutamate binding. (In C. elegans and Drosophila, invertebrate-specific subunits enable the flow of negative chloride 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 excitatory postsynaptic current (EPSC). This current is depolarizing and, if enough glutamate receptors are activated, may trigger an action potential in the postsynaptic neuron. All produce excitatory postsynaptic 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-dependent block, which is removed by outward flow of positive current.JOURNAL, Johnson JW, Ascher P, Voltage-dependent block by intracellular Mg2+ of N-methyl-D-aspartate-activated channels, Biophys. J., 57, 5, 1085–90, May 1990, 1692749, 1280813, 10.1016/S0006-3495(90)82626-6, 1990BpJ....57.1085J, 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+,JOURNAL, Crowder JM, Croucher MJ, Bradford HF, Collins JF, Excitatory amino acid receptors and depolarization-induced Ca2+ influx into hippocampal slices, J. Neurochem., 48, 6, 1917–24, June 1987, 2437250, 10.1111/j.1471-4159.1987.tb05756.x, 12586076, which is an important cation in the nervous systemBOOK, Gover TD, Moreira TH, Weinreich D, Role of Calcium in Regulating Primary Sensory Neuronal Excitability, Sensory Nerves, 194, 563–87, 2009, 19655118, 10.1007/978-3-540-79090-7_16, Handbook of Experimental Pharmacology, 978-3-540-79089-1, and has been linked to gene regulation.JOURNAL, Barbado M, Fablet K, Ronjat M, De Waard M, Gene regulation by voltage-dependent calcium channels, Biochim. Biophys. Acta, 1793, 6, 1096–104, June 2009, 19250948, 10.1016/j.bbamcr.2009.02.004, 2807929,weblink The flow of Ca2+ through NMDA receptors is thought to cause both long-term potentiation (LTP, of synapse efficacy) and long-term depression (LTD) by transducing signaling cascades and regulating gene expression.

Metabotropic

Metabotropic glutamate receptors, which belong to subfamily C of G protein-coupled receptors are divided into three groups, with a total of eight subtypes (in mammals; this is not necessarily the case for most organisms). The mGluRs are composed of three distinct regions: the extracellular region, the transmembrane region, and the intracellular region.JOURNAL, Muto T, Tsuchiya D, Morikawa K, Jingami H, Structures of the extracellular regions of the group II/III metabotropic glutamate receptors, Proc. Natl. Acad. Sci. U.S.A., 104, 10, 3759–64, March 2007, 17360426, 1820657, 10.1073/pnas.0611577104, 2007PNAS..104.3759M, free, The extracellular region is composed of a venus flytrap (VFT) module that binds glutamate,JOURNAL, Pin JP, Acher F, The metabotropic glutamate receptors: structure, activation mechanism and pharmacology, Curr Drug Targets CNS Neurol Disord, 1, 3, 297–317, June 2002, 12769621, 10.2174/1568007023339328, and a cysteine-rich domain that is thought to play a role in transmitting the conformational change induced by ligand 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.JOURNAL, Platt SR, The role of glutamate in central nervous system health and disease--a review, Vet. J., 173, 2, 278–86, 2007, 16376594, 10.1016/j.tvjl.2005.11.007, Because of this, mGluRs can both increase or decrease the excitability of the postsynaptic cell, thereby causing a wide range of physiological effects.

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.JOURNAL, Kinnamon SC, Vandenbeuch A, Receptors and transduction of umami taste stimuli, Ann. N. Y. Acad. Sci., 1170, 1, 55–9, July 2009, 19686108, 10.1111/j.1749-6632.2009.04106.x, 2009NYASA1170...55K, 20962248, 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.JOURNAL, Gill SS, Pulido OM, Mueller RW, McGuire PF, Molecular and immunochemical characterization of the ionotropic glutamate receptors in the rat heart, Brain Res. Bull., 46, 5, 429–34, July 1998, 9739005, 10.1016/S0361-9230(98)00012-4, 36044371, Glutamate receptors are (as mentioned above) also expressed in pancreatic islet cells.JOURNAL, Weaver CD, Yao TL, Powers AC, Verdoorn TA, Differential expression of glutamate receptor subtypes in rat pancreatic islets, J. Biol. Chem., 271, 22, 12977–84, May 1996, 8662728, 10.1074/jbc.271.22.12977, 36816887, free, AMPA iGluRs modulate the secretion of insulin and glucagon in the pancreas, opening the possibility of treatment of diabetes via glutamate receptor antagonists.JOURNAL, Bertrand G, Gross R, Puech R, Loubatières-Mariani MM, Bockaert J, Glutamate stimulates glucagon secretion via an excitatory amino acid receptor of the AMPA subtype in rat pancreas, Eur. J. Pharmacol., 237, 1, 45–50, June 1993, 7689469, 10.1016/0014-2999(93)90091-U, JOURNAL, Weaver CD, Gundersen V, Verdoorn TA, A high affinity glutamate/aspartate transport system in pancreatic islets of Langerhans modulates glucose-stimulated insulin secretion, J. Biol. Chem., 273, 3, 1647–53, January 1998, 9430708, 10.1074/jbc.273.3.1647, 27129532, free, 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.JOURNAL, Carlton SM, Hargett GL, Coggeshall RE, Localization and activation of glutamate receptors in unmyelinated axons of rat glabrous skin, Neurosci. Lett., 197, 1, 25–8, September 1995, 8545047, 10.1016/0304-3940(95)11889-5, 44486341,

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 antibody or autoantigen activity associated with glutamate receptors or their subunit genes (e.g. GluR3 in Rasmussen's encephalitis,JOURNAL, Carlson NG, Gahring LC, Twyman RE, Rogers SW, Identification of amino acids in the glutamate receptor, GluR3, important for antibody-binding and receptor-specific activation, J. Biol. Chem., 272, 17, 11295–301, April 1997, 9111034, 10.1074/jbc.272.17.11295, 7239019, free, and GluR2 in nonfamilial olivopontocerebellar degeneration).JOURNAL, Gahring LC, Rogers SW, Twyman RE, Autoantibodies to glutamate receptor subunit GluR2 in nonfamilial olivopontocerebellar degeneration, Neurology, 48, 2, 494–500, February 1997, 9040745, 10.1212/wnl.48.2.494, 20274921, In 1994 GluR3 was shown to act as an autoantigen in Rasmussen's encephalitis, leading to speculation that autoimmune activity might underlie the condition.Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis - 1994 Such findings "suggest" links between glutamate receptors and autoimmune interactions are possible and may be significant in some degenerative diseases, however the exact role of such antibodies in disease manifestation is still not entirely known.JOURNAL, He XP, Patel M, Whitney KD, Janumpalli S, Tenner A, McNamara JO, Glutamate receptor GluR3 antibodies and death of cortical cells, Neuron, 20, 1, 153–63, January 1998, 9459451, 10.1016/S0896-6273(00)80443-2, 1742781, free,

Excitotoxicity

Overstimulation of glutamate receptors causes neurodegeneration and neuronal damage through a process called excitotoxicity. 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.JOURNAL, Dubinsky JM, Intracellular calcium levels during the period of delayed excitotoxicity, J. Neurosci., 13, 2, 623–31, February 1993, 8093901, 6576661, 10.1523/JNEUROSCI.13-02-00623.1993, 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.JOURNAL, Manev H, Favaron M, Guidotti A, Costa E, Delayed increase of Ca2+ influx elicited by glutamate: role in neuronal death, Mol. Pharmacol., 36, 1, 106–12, July 1989, 2568579, Ingestion of or exposure to excitotoxins that act on glutamate receptors can induce excitotoxicity and cause toxic effects on the central nervous system.JOURNAL, Meldrum B, Amino acids as dietary excitotoxins: a contribution to understanding neurodegenerative disorders, Brain Res. Brain Res. Rev., 18, 3, 293–314, 1993, 8401596, 10.1016/0165-0173(93)90014-Q, 11003515, 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.JOURNAL, Aoyama K, Watabe M, Nakaki T, Regulation of neuronal glutathione synthesis, J. Pharmacol. Sci., 108, 3, 227–38, November 2008, 19008644, 10.1254/jphs.08R01CR, free, 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.JOURNAL, Markowitz AJ, White MG, Kolson DL, Jordan-Sciutto KL, Cellular interplay between neurons and glia: toward a comprehensive mechanism for excitotoxic neuronal loss in neurodegeneration, Cellscience, 4, 1, 111–146, July 2007, 19122795, 2613343, 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.JOURNAL, Nicholls DG, 14826555, Spare respiratory capacity, oxidative stress and excitotoxicity, Biochem. Soc. Trans., 37, Pt 6, 1385–8, December 2009, 19909281, 10.1042/BST0371385,

Neurodegeneration

In the case of traumatic brain injury or cerebral ischemia (e.g., cerebral infarction or hemorrhage), acute neurodegeneration caused by excitotoxicity may spread to proximal neurons through two processes. Hypoxia and hypoglycemia trigger bioenergetic failure; mitochondria stop producing ATP energy. Na+/K+-ATPase 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.JOURNAL, Hirsch JA, Gibson GE, Selective alteration of neurotransmitter release by low oxygen in vitro, Neurochem. Res., 9, 8, 1039–49, August 1984, 6149480, 10.1007/BF00964800, 22594469, In addition, cell death via lysis or apoptosis releases cytoplasmic glutamate outside of the ruptured cell.JOURNAL, Obrenovitch TP, Richards DA, Extracellular neurotransmitter changes in cerebral ischaemia, Cerebrovasc Brain Metab Rev, 7, 1, 1–54, 1995, 7742171, These two forms of glutamate release cause a continual cascade of excitotoxic cell death and further increased extracellular glutamate concentrations.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.JOURNAL, Beal MF, Mechanisms of excitotoxicity in neurologic diseases, FASEB J., 6, 15, 3338–44, December 1992, 1464368, 10.1096/fasebj.6.15.1464368, 22958157, free,

Conditions with demonstrated associations to glutamate receptors

A number of diseases in humans have a proven association with genetic mutations of glutamate receptor genes, or autoantigen/antibody interactions with glutamate receptors or their genes. Glutamate receptors and impaired regulation (in particular, those resulting in excessive glutamate levels) are also one cause of excitotoxicity (described above), which itself has been implicated or associated with a number of specific neurodegenerative conditions where neural cell death or degradation within the brain occurs over time.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.JOURNAL, Nechifor M, Magnesium in drug dependences, Magnesium Research, 21, 1, 5–15, March 2008, 18557129, 10.1684/mrh.2008.0124,weblink 31 January 2024, Glutamate receptors have been found to have an influence in ischemia/stroke, seizures, Parkinson's disease, Huntington's disease, and aching,WEB,weblink Glutamate Receptor Summary Report, CureHunter, 2009-12-07, addictionJOURNAL, Vadasz C, Saito M, Gyetvai BM, Oros M, Szakall I, Kovacs KM, Prasad VV, Toth R, Glutamate receptor metabotropic 7 is cis-regulated in the mouse brain and modulates alcohol drinking., Genomics, 90, 6, 690–702, 2007, 10.1016/j.ygeno.2007.08.006, 17936574, free, and an association with both ADHDJOURNAL, Elia J, Glessner JT, Wang K, Takahashi N, Shtir CJ, Hadley D, Sleiman PM, Zhang H, Kim CE, Robison R, Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder, Nat. Genet., 44, 1, 78–84, January 2012, 22138692, 4310555, 10.1038/ng.1013, etal,

• WEB, December 5, 2011, Glutamate Receptor Gene Changes Identified in ADHD, Genetic Engineering & Biotechnology News,weblink and autism.JOURNAL, Schmeisser MJ, Ey E, Wegener S, Bockmann J, Stempel AV, Kuebler A, Janssen AL, Udvardi PT, Shiban E, Spilker C, Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2, Nature, 486, 7402, 256–60, June 2012, 22699619, 10.1038/nature11015, etal, 2012Natur.486..256S, 4412353,
• PRESS RELEASE, 3 May 2012, Of Mice and Men: Characterization of a new autism gene, AlphaGalileo Foundation,weblinkweblink" title="web.archive.org/web/20120517133912weblink">weblink 2012-05-17,

In most cases these are areas of ongoing research.

Aching

Hyperalgesia 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 administration. Since spinal NMDA receptors link the area of pain to the brain's pain processing center, the thalamus, these glutamate receptors are a prime target for treatment. One proposed way to cope with the pain is subconsciously through the visualization technique.WEB, Glutamate - A Pain Transmitter Your Subconscious May Be Able To Limit, Plumb B, EzineArticles.com, {{self-published inline|date=August 2019}}{{Unreliable source?|date=August 2019}}

Attention deficit hyperactivity disorder (ADHD)

In 2006 the glutamate receptor subunit gene GRIN2B (responsible for key functions in memory and learning) was associated with ADHD.JOURNAL, Dorval KM, Wigg KG, Crosbie J, Tannock R, Kennedy JL, Ickowicz A, Pathare T, Malone M, Schachar R, Barr CL, Association of the glutamate receptor subunit gene GRIN2B with attention-deficit/hyperactivity disorder, Genes Brain Behav., 6, 5, 444–52, July 2007, 17010153, 10.1111/j.1601-183X.2006.00273.x, 4833492, This followed earlier studies showing a link between glutamate modulation and hyperactivity (2001),JOURNAL, Gainetdinov RR, Mohn AR, Bohn LM, Caron MG, Glutamatergic modulation of hyperactivity in mice lacking the dopamine transporter, Proc. Natl. Acad. Sci. U.S.A., 98, 20, 11047–54, September 2001, 11572967, 58681, 10.1073/pnas.191353298, 2001PNAS...9811047G, free, and then between the SLC1A3 solute carrier gene-encoding part of the glutamate transporter process that mapped to chromosome 5 (5p12) noted in multiple ADHD genome scans.JOURNAL, Turic D, Langley K, Williams H, Norton N, Williams NM, Moskvina V, Van den Bree MB, Owen MJ, Thapar A, O'Donovan MC, A family based study implicates solute carrier family 1-member 3 (SLC1A3) gene in attention-deficit/hyperactivity disorder, Biol. Psychiatry, 57, 11, 1461–6, June 2005, 15950021, 10.1016/j.biopsych.2005.03.025, 26867098, Further mutations to four different metabotropic glutamate receptor genes were identified in a study of 1013 children with ADHD compared to 4105 controls with non-ADHD, replicated in a subsequent study of 2500 more patients. Deletions and duplications affected GRM1, GRM5, GRM7 and GRM8. The study concluded that "CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10−9)", "over 200 genes interacting with glutamate receptors […] were collectively affected by CNVs", "major hubs of the (affected genes') network include TNIK50, GNAQ51, and CALM", and "the fact that children with ADHD are more likely to have alterations in these genes reinforces previous evidence that the GRM pathway is important in ADHD".A SciBX article in January 2012 commented that "UPenn and MIT teams have independently converged on mGluRs as players in ADHD and autism. The findings suggest agonizing mGluRs in patients with ADHD."JOURNAL, Osherovich L, Fine-tuning mGluRs, Science-Business EXchange, 2012, 5, 1, 3, 10.1038/scibx.2012.3, free,

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.JOURNAL, Chez MG, Burton Q, Dowling T, Chang M, Khanna P, Kramer C, Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability, Journal of Child Neurology, 22, 5, 574–9, May 2007, 17690064, 10.1177/0883073807302611, 41428656, JOURNAL, Erickson CA, Posey DJ, Stigler KA, Mullett J, Katschke AR, McDougle CJ, A retrospective study of memantine in children and adolescents with pervasive developmental disorders, Psychopharmacology, 191, 1, 141–7, March 2007, 17016714, 10.1007/s00213-006-0518-9, 13128356, Research is underway on the effects of memantine in adults with autism spectrum disorders.{{ClinicalTrialsGov|NCT01333865|A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders}}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."

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, 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, to be specific the malfunctioning NMDA glutamate receptors during early stages of the disease.JOURNAL, Trudeau F, Gagnon S, Massicotte G, Hippocampal synaptic plasticity and glutamate receptor regulation: influences of diabetes mellitus, Eur. J. Pharmacol., 490, 1–3, 177–86, April 2004, 15094084, 10.1016/j.ejphar.2004.02.055, 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. 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.JOURNAL, Diguet E, Fernagut PO, Normand E, Centelles L, Mulle C, Tison F, Experimental basis for the putative role of GluR6/kainate glutamate receptor subunit in Huntington's disease natural history, Neurobiol. Dis., 15, 3, 667–75, April 2004, 15056475, 10.1016/j.nbd.2003.12.010, 41752581, 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. Using folic acid has been proposed as a possible treatment for Huntington's due to the inhibition it exhibits on homocysteine, which increases vulnerability of nerve cells to glutamate.JOURNAL, Wu J, Tang T, Bezprozvanny I, Evaluation of clinically relevant glutamate pathway inhibitors in in vitro model of Huntington's disease, Neurosci. Lett., 407, 3, 219–23, October 2006, 16959411, 10.1016/j.neulet.2006.08.036, 18046017,

• WEB, 2006-10-31, Test reveals effectiveness of potential Huntington's disease drugs, Innovations Report,weblink This could decrease the effect glutamate has on glutamate receptors and reduce cell response to a safer level, not reaching excitotoxicity.

Ischemia

During ischemia, the brain has been observed to have an unnaturally high concentration of extracellular glutamate.JOURNAL, Nishizawa Y., Glutamate release and neuronal damage in ischemia, Life Sci., 69, 4, 369–81, 2001, 11459428, 10.1016/S0024-3205(01)01142-0, This is linked to an inadequate supply of ATP, which drives the glutamate transport levels that keep the concentrations of glutamate in balance.WEB,weblink Sources of Glutamate in Ischemia, Ottersen OP, Neurodegeneration Research Group, University of Oslo,weblink" title="web.archive.org/web/19981202040728weblink">weblink 1998-12-02, dead, 2009-12-07, 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. 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.JOURNAL, Meldrum BS, Glutamate as a neurotransmitter in the brain: review of physiology and pathology, J. Nutr., 130, 4S Suppl, 1007S–15S, 2000, 10736372, 10.1093/jn/130.4.1007s, free,

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.JOURNAL, Bolton C, Paul C, Glutamate receptors in neuroinflammatory demyelinating disease, Mediators of Inflammation, 2006, 2, 93684, 2006, 16883070, 1592583, 10.1155/MI/2006/93684, free, 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.

Parkinson's disease (Parkinsonism)

Late onset neurological disorders, such as Parkinson's disease, may be partially due to glutamate binding NMDA and AMPA glutamate receptors. In vitro spinal cord cultures with glutamate transport inhibitors led to degeneration of motor neurons, which was counteracted by some AMPA receptor antagonists such as 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 striatum.JOURNAL, Cuomo D, etal, Metabotropic glutamate receptor subtype 4 selectively modulates both glutamate and GABA transmission in the striatum: implications for Parkinson's disease treatment, J Neurochem, 109, 4, 1096–105, 2009, 19519781, 10.1111/j.1471-4159.2009.06036.x, GABA, 23414211, free,

Rasmussen's encephalitis

In 1994, GluR3 was shown to act as an autoantigen in Rasmussen's encephalitis, leading to speculation that autoimmune activity might underlie the condition.

Schizophrenia

In schizophrenia, the expression of the mRNA for the NR2A subunit of the NMDA glutamate receptor was found to be decreased in a subset of inhibitory interneurons in the cerebral cortex.JOURNAL, Bitanihirwe BK, Lim MP, Kelley JF, Kaneko T, Woo TU, Glutamatergic deficits and parvalbumin-containing inhibitory neurons in the prefrontal cortex in schizophrenia, BMC Psychiatry, 9, 71, November 2009, 19917116, 10.1186/1471-244X-9-71, 2784456, free, This is suggested by upregulation of GABA, 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 (PV), which exhibits fast-spiking firing properties and target the perisomatic (basket cells) and axo-axonic (chandelier cells) compartments of pyramidal neurons. The study found the density of NR2A mRNA-expressing PV neurons was decreased by as much as 50% in subjects with schizophrenia.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. 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,JOURNAL, Woo TU, Shrestha K, Lamb D, Minns MM, Benes FM, N-Methyl-D-Aspartate Receptor and Calbindin-Containing Neurons in the Anterior Cingulate Cortex in Schizophrenia and Bipolar Disorder, Biol Psychiatry, 64, 9, 803–809, April 2008, 18585682, 10.1016/j.biopsych.2008.04.034, 3877780, 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.JOURNAL, Woo TU, Shrestha K, Armstrong C, Minns MM, Walsh JP, Benes FM, Differential alterations of kainate receptor subunits in inhibitory interneurons in the anterior cingulate cortex in schizophrenia and bipolar disorder, Schizophrenia Research, 96, 1–3, 46–61, August 2007, 17698324, 10.1016/j.schres.2007.06.023, 2712609, Current research is targeting 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.JOURNAL, de Lucena D, Fernandes BS, Berk M, etal, 26374475, Improvement of negative and positive symptoms in treatment-refractory schizophrenia: a double-blind, randomized, placebo-controlled trial with memantine as add-on therapy to clozapine, J Clin Psychiatry, 70, 10, 1416–23, October 2009, 19906345, 10.4088/JCP.08m04935gry, Furthermore, administration of noncompetitive NMDA receptor antagonists have been tested on rat models. Scientists have 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.JOURNAL, López-Gil X, Artigas F, Adell A, Unraveling Monoamine Receptors Involved in the Action of Typical and Atypical Antipsychotics on Glutamatergic and Serotonergic Transmission in Prefrontal Cortex, Curr. Pharm. Des., 16, 5, 502–15, November 2009, 19909228, 10.2174/138161210790361416, 10261/77721, free,

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.JOURNAL, Chapman AG, Glutamate and epilepsy, J. Nutr., 130, 4S Suppl, 1043S–5S, April 2000, 10736378, 10.1093/jn/130.4.1043S, free, 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.JOURNAL, Moldrich RX, Chapman AG, De Sarro G, Meldrum BS, Glutamate metabotropic receptors as targets for drug therapy in epilepsy, Eur. J. Pharmacol., 476, 1–2, 3–16, August 2003, 12969743, 10.1016/S0014-2999(03)02149-6,

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:BOOK, Gillessen T, Budd SL, Lipton SA, Excitatory Amino Acid Neurotoxicity, Molecular and Cellular Biology of Neuroprotection in the CNS, 513, 3–40, 12575816, 10.1007/978-1-4615-0123-7_1, Advances in Experimental Medicine and Biology, 2003, 978-1-4613-4934-1,

• 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
• Hyperhomocysteinemia and 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

• Antiglutamate receptor antibodies
• Glutamate receptor-interacting protein
• N-Methyl-D-aspartic acid

References

{{Reflist|35em}}

External links

• {{MeshName|Glutamate+Receptors}}
• WEB,weblink Metabotropic Glutamate Receptors, IUPHAR Database of Receptors and Ion Channels, International Union of Basic and Clinical Pharmacology, 2007-10-25, 2016-03-03,weblink" title="web.archive.org/web/20160303201514weblink">weblink dead,

{{Ligand-gated ion channels}}{{G protein-coupled receptors}}{{Glutamatergics}}