Glutamate (neurotransmitter)

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Glutamate
L-Glutamate Structural Formula
Clinical data
Synonyms GLU (abbreviation), L-Glutamate
Physiological data
Source tissues almost every part of the nervous system
Target tissues system-wide
Receptors NMDA, AMPA, kainate, mGluR
Agonists NMDA, AMPA, kainic acid
Antagonists AP5, ketamine, CNQX, kynurenic acid
Precursor mainly dietary sources
Metabolism glutamate dehydrogenase
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
KEGG

In neuroscience, glutamate refers to the anion of glutamic acid in its role as a neurotransmitter: a chemical that nerve cells use to send signals to other cells. It is by a wide margin the most abundant neurotransmitter in the vertebrate nervous system.[1] It is used by every major excitatory function in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain. It also serves as the primary neurotransmitter for some localized brain regions, such as cerebellum granule cells.

Biochemical receptors for glutamate fall into three major classes, known as AMPA receptors, NMDA receptors, and metabotropic glutamate receptors. A fourth class, known as kainate receptors, are similar in many respects to AMPA receptors, but much less abundant. Many synapses use multiple types of glutamate receptors. AMPA receptors are ionotropic receptors specialized for fast excitation: in many synapses they produce excitatory electrical responses in their targets a fraction of a millisecond after being stimulated. NMDA receptors are also ionotropic, but they differ from AMPA receptors in being permeable, when activated, to calcium. Their properties make them particularly important for learning and memory. Metabotropic receptors act through second messenger systems to create slow, sustained effects on their targets.

Because of its role in synaptic plasticity, glutamate is involved in cognitive functions such as learning and memory in the brain.[2] The form of plasticity known as long-term potentiation takes place at glutamatergic synapses in the hippocampus, neocortex, and other parts of the brain. Glutamate works not only as a point-to-point transmitter, but also through spill-over synaptic crosstalk between synapses in which summation of glutamate released from a neighboring synapse creates extrasynaptic signaling/volume transmission.[3] In addition, glutamate plays important roles in the regulation of growth cones and synaptogenesis during brain development.

Biosynthesis[edit]

Glutamate is a major constituent of a wide variety of proteins; consequently it is one of the most abundant amino acids in the human body.[1] Under ordinary conditions enough is obtained from the diet that there is no need for any to be synthesized. Nevertheless, glutamate is formally classified as a non-essential amino acid, because it can be synthesized from alpha-Ketoglutaric acid, which is produced as part of the citric acid cycle by a series of reactions whose starting point is citrate. Glutamate cannot cross the blood-brain barrier unassisted, but it is actively transported into the nervous system by a high affinity transport system, which maintains its concentration in brain fluids at a fairly constant level.[4]

Glutamate is synthesized in the central nervous system from glutamine as part of the glutamate-glutamine cycle by the enzyme glutaminase. This can occur in the presynaptic neuron or in neighboring glial cells.

Glutamate itself serves as metabolic precursor for the neurotransmitter GABA, via the action of the enzyme glutamate decarboxylase.

Cellular effects[edit]

Glutamate receptors in the mammal brain
Family Type Mechanism
AMPA Ionotropic Increase membrane permeability for sodium and potassium
kainate Ionotropic Increase membrane permeability for sodium and potassium
NMDA Ionotropic, voltage gated Increase membrane permeability for calcium
metabotropic
Group I
Gq-coupled Increase IP3 and diacyl glycerol by activating phospholipase C
metabotropic
Group II
Gi/G0-coupled Decrease intracellular levels of cAMP by inhibiting adenylate cyclase
metabotropic
Group III
Gi/G0-coupled Decrease intracellular levels of cAMP by inhibiting adenylate cyclase

Glutamate exerts its effects by binding to and activating cell surface receptors. In mammals, four families of glutamate receptors have been identified, known as AMPA receptors, kainate receptors, NMDA receptors, and metabotropic glutamate receptors. The first three families are ionotropic, meaning that when activated they open membrane channels that allow ions to pass through. The metabotropic family are G protein-coupled receptors, meaning that they exert their effects via a complex second messenger system.

Disease, disabilities, and pharmacology[edit]

Glutamate transporters, EAAT and VGLUT, are found in neuronal and glial membranes. They rapidly remove glutamate from the extracellular space. In brain injury or disease, they often work in reverse, and excess glutamate can accumulate outside cells. This process causes calcium ions to enter cells via NMDA receptor channels, leading to neuronal damage and eventual cell death, and is called excitotoxicity.[5] The mechanisms of cell death include

  • Ca2+-concentration regulates different mitochondrial functions and upon increasing uncontrollably, the excessively high intracellular Ca2+-concentration can damage mitochondria.[6]
  • Ca2+-concentration increases intracellular nitric oxide (NO) concentration. Excessive NO-molecules form free radicals and thus increase cell's oxidative stress.[7]
  • Glutamate or Ca2+ mediate promotion of transcription factors for pro-apoptotic genes, or downregulation of transcription factors for anti-apoptotic genes. Thus the net effect of increased Glu/Ca2+-concentration is cell apoptosis.[8]

Excitotoxicity due to excessive glutamate release and impaired uptake occurs as part of the ischemic cascade and is associated with stroke,[9] autism,[10] some forms of intellectual disability, and diseases such as amyotrophic lateral sclerosis, lathyrism, and Alzheimer's disease.[9][11] In contrast, decreased glutamate release is observed under conditions of classical phenylketonuria[12] leading to developmental disruption of glutamate receptor expression.[13]

Glutamic acid has been implicated in epileptic seizures. Microinjection of glutamic acid into neurons produces spontaneous depolarisations around one second apart, and this firing pattern is similar to what is known as paroxysmal depolarizing shift in epileptic attacks. This change in the resting membrane potential at seizure foci could cause spontaneous opening of voltage-activated calcium channels, leading to glutamic acid release and further depolarization.[citation needed]

Comparative biology and evolution[edit]

Glutamate functions as a neurotransmitter in every type of animal that has a nervous system, including ctenophores (comb jellies), which branched off from other phyla at an early stage in evolution and lack the other neurotransmitters found ubiquitously among animals, including serotonin and acetylcholine.[14] Rather, ctenophores have functionally distinct types of ionotropic glutamate receptors,[14] such that activation of these receptors may trigger muscle contraction and other responses.[14]

Sponges do not have a nervous system, but also make use of glutamate for cell-to-cell signalling. Sponges possess metabotropic glutamate receptors, and application of glutamate to a sponge can trigger a whole-body response that sponges use to rid themselves of contaminants.[15] The genome of Trichoplax, a primitive organism that also lacks a nervous system, contains numerous metabotropic glutamate receptors, but their function is not yet known.[16]

In arthropods and nematodes, glutamate stimulates glutamate-gated chloride channels.[citation needed] The β subunits of the receptor respond with very high affinity to glutamate and glycine.[17] Targeting these receptors has been the therapeutic goal of anthelmintic therapy using avermectins. Avermectins target the alpha subunit of glutamate-gated chloride channels with high affinity.[18] These receptors have also been described in arthropods, such as Drosophila melanogaster[19] and Lepeophtheirus salmonis.[20] Irreversible activation of these receptors with avermectins results in hyperpolarization at synapses and neuromuscular junctions resulting in flaccid paralysis and death of nematodes and arthropods.

History[edit]

The presence of glutamate in every part of the body as a building-block for protein made its special role in the nervous system difficult to recognize: its function as a neurotransmitter was not generally accepted until the 1970s, decades after the identification of acetylcholine, norepinephrine, and serotonin as neurotransmitters.[21] The first suggestion that glutamate might function as a transmitter came from T. Hayoshi in 1952, who was motivated by the finding that injections of glutamate into the cerebral ventricles of dogs could cause them to have seizures.[21][22] Other support for this idea soon appeared, but the majority of physiologists were skeptical, for a variety of theoretical and empirical reasons. One of the most common reasons for skepticism was the universality of glutamate's excitatory effects in the central nervous system, which seemed inconsistent with the specificity expected of a neurotransmitter.[21] Other reasons for skepticism included a lack of known antagonists and the absence of a known mechanism for inactivation. A series of discoveries during the 1970s resolved most of these doubts, and by 1980 the compelling nature of the evidence was almost universally recognized.[21]

References[edit]

  1. ^ a b Meldrum BS (April 2000). "Glutamate as a neurotransmitter in the brain: review of physiology and pathology" (PDF). The Journal of Nutrition. 130 (4S Suppl): 1007S–15S. doi:10.1093/jn/130.4.1007s. PMID 10736372. 
  2. ^ McEntee WJ, Crook TH (1993). "Glutamate: its role in learning, memory, and the aging brain". Psychopharmacology. 111 (4): 391–401. doi:10.1007/BF02253527. PMID 7870979. 
  3. ^ Okubo Y, Sekiya H, Namiki S, Sakamoto H, Iinuma S, Yamasaki M, Watanabe M, Hirose K, Iino M (April 2010). "Imaging extrasynaptic glutamate dynamics in the brain". Proceedings of the National Academy of Sciences of the United States of America. 107 (14): 6526–31. doi:10.1073/pnas.0913154107. PMC 2851965Freely accessible. PMID 20308566. 
  4. ^ Smith QR (April 2000). "Transport of glutamate and other amino acids at the blood-brain barrier". The Journal of Nutrition. 130 (4S Suppl): 1016S–22S. PMID 10736373. 
  5. ^ Shigeri Y, Seal RP, Shimamoto K (July 2004). "Molecular pharmacology of glutamate transporters, EAATs and VGLUTs". Brain Research. Brain Research Reviews. 45 (3): 250–65. doi:10.1016/j.brainresrev.2004.04.004. PMID 15210307. 
  6. ^ Duchen, Michael R. (2012-07-01). "Mitochondria, calcium-dependent neuronal death and neurodegenerative disease". Pflügers Archiv - European Journal of Physiology. 464 (1): 111–121. doi:10.1007/s00424-012-1112-0. ISSN 0031-6768. PMC 3387496Freely accessible. PMID 22615071. 
  7. ^ Murphy, Michael P (1999-05-05). "Nitric oxide and cell death". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1411 (2): 401–414. doi:10.1016/s0005-2728(99)00029-8. 
  8. ^ Dong, Xiao-xia; Wang, Yan; Qin, Zheng-hong (2009-04-03). "Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases". Acta Pharmacologica Sinica. 30 (4): 379–387. doi:10.1038/aps.2009.24. ISSN 1671-4083. PMC 4002277Freely accessible. PMID 19343058. 
  9. ^ a b Robert Sapolsky (2005). "Biology and Human Behavior: The Neurological Origins of Individuality, 2nd edition". The Teaching Company. see pages 19 and 20 of Guide Book 
  10. ^ Shinohe A, Hashimoto K, Nakamura K, Tsujii M, Iwata Y, Tsuchiya KJ, Sekine Y, Suda S, Suzuki K, Sugihara G, Matsuzaki H, Minabe Y, Sugiyama T, Kawai M, Iyo M, Takei N, Mori N (December 2006). "Increased serum levels of glutamate in adult patients with autism". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 30 (8): 1472–7. doi:10.1016/j.pnpbp.2006.06.013. PMID 16863675. 
  11. ^ Hynd MR, Scott HL, Dodd PR (October 2004). "Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease". Neurochemistry International. 45 (5): 583–95. doi:10.1016/j.neuint.2004.03.007. PMID 15234100. 
  12. ^ Glushakov AV, Dennis DM, Sumners C, Seubert CN, Martynyuk AE (April 2003). "L-phenylalanine selectively depresses currents at glutamatergic excitatory synapses". Journal of Neuroscience Research. 72 (1): 116–24. doi:10.1002/jnr.10569. PMID 12645085. 
  13. ^ Glushakov AV, Glushakova O, Varshney M, Bajpai LK, Sumners C, Laipis PJ, Embury JE, Baker SP, Otero DH, Dennis DM, Seubert CN, Martynyuk AE (February 2005). "Long-term changes in glutamatergic synaptic transmission in phenylketonuria". Brain. 128 (Pt 2): 300–7. doi:10.1093/brain/awh354. PMID 15634735. 
  14. ^ a b c Moroz LL, Kocot KM, Citarella MR, Dosung S, Norekian TP, Povolotskaya IS, Grigorenko AP, Dailey C, Berezikov E, Buckley KM, Ptitsyn A, Reshetov D, Mukherjee K, Moroz TP, Bobkova Y, Yu F, Kapitonov VV, Jurka J, Bobkov YV, Swore JJ, Girardo DO, Fodor A, Gusev F, Sanford R, Bruders R, Kittler E, Mills CE, Rast JP, Derelle R, Solovyev VV, Kondrashov FA, Swalla BJ, Sweedler JV, Rogaev EI, Halanych KM, Kohn AB (June 2014). "The ctenophore genome and the evolutionary origins of neural systems". Nature. 510 (7503): 109–14. doi:10.1038/nature13400. PMC 4337882Freely accessible. PMID 24847885. 
  15. ^ Leys SP (February 2015). "Elements of a 'nervous system' in sponges". The Journal of Experimental Biology. 218 (Pt 4): 581–91. doi:10.1242/jeb.110817. PMID 25696821. 
  16. ^ Krishnan A, Schiöth HB (February 2015). "The role of G protein-coupled receptors in the early evolution of neurotransmission and the nervous system". The Journal of Experimental Biology. 218 (Pt 4): 562–71. doi:10.1242/jeb.110312. PMID 25696819. 
  17. ^ Laughton DL, Wheeler SV, Lunt GG, Wolstenholme AJ (May 1995). "The beta-subunit of Caenorhabditis elegans avermectin receptor responds to glycine and is encoded by chromosome 1". Journal of Neurochemistry. 64 (5): 2354–7. doi:10.1046/j.1471-4159.1995.64052354.x. PMID 7536811. 
  18. ^ Cully DF, Vassilatis DK, Liu KK, Paress PS, Van der Ploeg LH, Schaeffer JM, Arena JP (October 1994). "Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans". Nature. 371 (6499): 707–11. doi:10.1038/371707a0. PMID 7935817. 
  19. ^ Cully DF, Paress PS, Liu KK, Schaeffer JM, Arena JP (1996). "Identification of a Drosophila melanogaster glutamate-gated chloride channel sensitive to the antiparasitic agent avermectin". The Journal of Biological Chemistry. 271 (33): 20187–91. doi:10.1074/jbc.271.33.20187. PMID 8702744. 
  20. ^ Tribble ND, Burka JF, Kibenge FS (April 2007). "Identification of the genes encoding for putative gamma aminobutyric acid (GABA) and glutamate-gated chloride channel (GluCl) alpha receptor subunits in sea lice (Lepeophtheirus salmonis)". Journal of Veterinary Pharmacology and Therapeutics. 30 (2): 163–7. doi:10.1111/j.1365-2885.2007.00823.x. PMID 17348903. 
  21. ^ a b c d Watkins JC (2000). "l-glutamate as a central neurotransmitter: looking back". Biochemical Society Transactions. 28 (4): 297–309. doi:10.1042/0300-5127:0280297. PMID 10961913. 
  22. ^ Hayashi, T. (November 1952). "A physiological study of epileptic seizures following cortical stimulation in animals and its application to human clinics". The Japanese Journal of Physiology. 3 (1): 46–64. doi:10.2170/jjphysiol.3.46. ISSN 0021-521X. PMID 13034377.