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[[File:L-Glutamate.svg|250px|thumb|right|L-glutamate molecule]]
[[File:L-Glutamate.svg|250px|thumb|right|L-glutamate molecule]]
'''Glutamate''', also known as '''glutamic acid''', is one of the principal excitatory neurotransmitters in the human central nervous system (CNS).  
'''Glutamate''', also known as '''glutamic acid''', is one of the principal excitatory neurotransmitters in the human central nervous system (CNS).  
It is the most abundant neurotransmitter in vertebrates and is involved in every major excitatory function, accounting in total for well over 90% of the synaptic connections in the human brain.<ref>Meldrum, B. S. (2000). Glutamate as a neurotransmitter in the brain: review of physiology and pathology. The Journal of Nutrition, 130(4), 1007S-1015S. https://doi.org/10.1093/jn/130.4.1007s.</ref>
It is the most abundant neurotransmitter in vertebrates and is involved in every major excitatory function, accounting in total for well over 90% of the synaptic connections in the human brain.<ref name="Meldrum2000">{{cite journal|last1=Meldrum|first1=Brian S.|title=Glutamate as a Neurotransmitter in the Brain: Review of Physiology and Pathology|journal=The Journal of Nutrition|volume=130|issue=4|year=2000|pages=1007S–1015S|issn=0022-3166|doi=10.1093/jn/130.4.1007S}}</ref>
Because of its role in synaptic plasticity, glutamate is involved in cognitive functions such as learning and memory.<ref>McEntee, W. J., & Crook, T. H. (1993). Glutamate: its role in learning, memory, and the aging brain. Psychopharmacology, 111(4), 391-401. https://doi.org/10.1007/BF02253527. PMID 7870979.</ref>


The receptors for glutamate can be divided into metabotropic and ionotropic glutamate receptors. Ionotopic glutamate receptors fall into three major classes, known as AMPA receptors (GluA1-GluA4), [[NMDA receptor|NMDA receptors]] (GluN1-GluN3), and kainate receptors (GluK1-GluK5).{{citation needed}}<ref>Graham L. Collingridge, Richard W. Olsen, John Peters, Michael Spedding,
Because of its role in synaptic plasticity, glutamate is involved in cognitive functions such as learning and memory.<ref name="McEnteeCrook1993">{{cite journal|last1=McEntee|first1=William J.|last2=Crook|first2=Thomas H.|title=Glutamate: its role in learning, memory, and the aging brain|journal=Psychopharmacology|volume=111|issue=4|year=1993|pages=391–401|issn=0033-3158|doi=10.1007/BF02253527}}</ref>


A nomenclature for ligand-gated ion channels,


Neuropharmacology,
The receptors for glutamate can be divided into metabotropic and ionotropic glutamate receptors. Ionotopic glutamate receptors fall into three major classes, known as AMPA receptors (GluA1-GluA4), [[NMDA receptor|NMDA receptors]] (GluN1-GluN3), and kainate receptors (GluK1-GluK5).{{citation needed}}<ref name="CollingridgeOlsen2009">{{cite journal|last1=Collingridge|first1=Graham L.|last2=Olsen|first2=Richard W.|last3=Peters|first3=John|last4=Spedding|first4=Michael|title=A nomenclature for ligand-gated ion channels|journal=Neuropharmacology|volume=56|issue=1|year=2009|pages=2–5|issn=00283908|doi=10.1016/j.neuropharm.2008.06.063}}</ref>


Volume 56, Issue 1,
Glutamate is a major constituent of a wide variety of proteins which makes it one of the most abundant amino acids in the human body.<ref name="Meldrum2000">{{cite journal|last1=Meldrum|first1=Brian S.|title=Glutamate as a Neurotransmitter in the Brain: Review of Physiology and Pathology|journal=The Journal of Nutrition|volume=130|issue=4|year=2000|pages=1007S–1015S|issn=0022-3166|doi=10.1093/jn/130.4.1007S}}</ref> It also serves as a metabolic precursor for the neurotransmitter [[GABA]], the main inhibitory neurotransmitter.
 
2009,
 
Pages 2-5,
 
ISSN 0028-3908,
 
<nowiki>https://doi.org/10.1016/j.neuropharm.2008.06.063</nowiki>.
 
(<nowiki>https://www.sciencedirect.com/science/article/pii/S0028390808002293</nowiki>)
 
Abstract: The ligand-gated ion channels that participate in fast synaptic transmission comprise the nicotinic acetylcholine, 5-hydroxytryptamine3 (5-HT3), γ-aminobutyric acidA (GABAA), glycine, ionotropic glutamate and P2X receptor families. A consistent and systematic nomenclature for the individual subunits that comprise these receptors and the receptors that result from their co-assembly is highly desirable. There is also a need to develop criteria that aid in deciding which of the vast number of heteromeric combinations of subunits that can be assembled in heterologous expression systems in vitro, are known, or likely, to exist as functional receptors in vivo. The aim of this short article is to summarize the progress being made by the nomenclature committee of IUPHAR (NC-IUPHAR) in formulating recommendations that attempt to address these issues.
 
Keywords: Ligand-gated ion channels; Nomenclature</ref>
 
Glutamate is a major constituent of a wide variety of proteins which makes it one of the most abundant amino acids in the human body.<ref>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. https://doi.org/10.1093/jn/130.4.1007s. PMID 10736372.</ref> It also serves as a metabolic precursor for the neurotransmitter [[GABA]], the main inhibitory neurotransmitter.


==Chemistry==
==Chemistry==
Glutamate generally exists as a negatively-charged carboxylate at pH values above 4.
In solutions, glutamate generally exists as a overall negatively-charged carboxylate at pH values above 4. As with other amino acids, it carries both a negatively charged carboxylate group and a positively charged amine, and its side chain has an additional carboxylate, giving it overall charge of -1 if completely ionised. It is one of the 20 proteogenic amino acids that serve as basic components of all proteins. Like all others, glutamate is an alpha amino acid, which means that its amine group is on the carbon that neighbors the carboxylic group, and an L-amino acid, referring to its "left handed" stereochemistry (in the more precise S/R naming system it would be (S)) <ref> Kennely P. J. and Rodwell, V. W, Amino Acids & Peptides (2018). In Harper's Illustrated Biochemistry, pp 14-22, LANGE</ref>.


In humans, glutamate is synthetised from alfa-keto glutarate, thus it is a non-essential amino acid. It is also a precursor for another amino acid, glutamine.
Because of its role as a neurotransmitter, glutamate concentration in the brain must be strictly regulated. It cannot easily cross the [[blood-brain barrier]] and most of it is synthetised de novo in brain cells and transported in the form of glutamine <ref>Hawkins RA. The blood-brain barrier and glutamate. Am J Clin Nutr. 2009 Sep;90(3):867S-874S. doi: 10.3945/ajcn.2009.27462BB. Epub 2009 Jul 1. PMID: 19571220; PMCID: PMC3136011.</ref>.
==Glutamate system==
==Glutamate system==
There are two categories of glutamate receptors, named for the mechanism that gives rise to the postsynaptic current; ionotropic and metabotropic. Ionotropic receptors work via the movement of ions in and out on ligand-gated ion channels. Metabotropic receptors work via their activation of secondary messenger chemicals. These chemicals eventually induce the postsynaptic current, either through their own action or by activating the ligand-gated ion channels.
There are two categories of glutamate receptors, named for the mechanism that gives rise to the postsynaptic current; ionotropic and metabotropic. Ionotropic receptors work via the movement of ions in and out on ligand-gated ion channels. Metabotropic receptors work via their activation of secondary messenger chemicals. These chemicals eventually induce the postsynaptic current, either through their own action or by activating the ligand-gated ion channels.
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*'''Agonists'''
*'''Agonists'''


A glutamate [[agonist]] is a chemical that binds to and activates a glutamate [[receptor]] and triggers a response, displaying full efficacy at that receptor. An example of this is [[theanine]], a weak agonist of the NMDA receptor.<ref>Wakabayashi C, Numakawa T, Ninomiya M, Chiba S, Kunugi H (2012). "Behavioral and molecular evidence for psychotropic effects in L-theanine". Psychopharmacology (Berl.). 219 (4): 1099–109. PMID 21861094. https://doi.org/10.1007/s00213-011-2440-z</ref>
A glutamate [[agonist]] is a chemical that binds to and activates a glutamate [[receptor]] and triggers a response, displaying full efficacy at that receptor. An example of this is [[theanine]], a weak agonist of the NMDA receptor.<ref name="WakabayashiNumakawa2011">{{cite journal|last1=Wakabayashi|first1=Chisato|last2=Numakawa|first2=Tadahiro|last3=Ninomiya|first3=Midori|last4=Chiba|first4=Shuichi|last5=Kunugi|first5=Hiroshi|title=Behavioral and molecular evidence for psychotropic effects in l-theanine|journal=Psychopharmacology|volume=219|issue=4|year=2011|pages=1099–1109|issn=0033-3158|doi=10.1007/s00213-011-2440-z}}</ref>. Because of the high expression and excitatory effects, NMDA receptor overactivation can cause seizures. Stronger agonists are therefore often pro-convulsant and neurotoxic <ref>Hanada T. Ionotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors. Biomolecules. 2020 Mar 18;10(3):464. doi: 10.3390/biom10030464. PMID: 32197322; PMCID: PMC7175173.</ref>.


*'''Positive Allosteric Modulators'''
*'''Positive Allosteric Modulators'''
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*'''Antagonists'''
*'''Antagonists'''


A glutamate receptor [[antagonist]] is a type of receptor drug that inhibits action at glutamate receptors. [[Alcohol|Ethanol]] acts as an antagonist of the NMDA, AMPA and kainate glutamate receptors, along with several antiepileptic drugs.{{citation needed}} The nootropic compound [[theanine]] is an antagonist of the AMPA and kainate receptors.<ref>Kakuda T (2002). "Neuroprotective effects of the green tea components theanine and catechins". Biol. Pharm. Bull. 25 (12): 1513–8. PMID 12499631. https://doi.org/10.1248/bpb.25.1513</ref> Many [[dissociatives|dissociative]] drugs are antagonists of the NMDA glutamate receptor, including [[ketamine]], [[MXE]], [[PCP]] and [[DXM]]. [[Tramadol]] and [[ibogaine]] are dual antagonists of the NMDA glutamate receptor and [[opioid]] receptors.{{citation needed}}  
A glutamate receptor [[antagonist]] is a type of receptor drug that inhibits action at glutamate receptors. [[Alcohol|Ethanol]] acts as an antagonist of the NMDA, AMPA and kainate glutamate receptors, along with several antiepileptic drugs.{{citation needed}} The nootropic compound [[theanine]] is an antagonist of the AMPA and kainate receptors.<ref name="Kakuda2002">{{cite journal|last1=Kakuda|first1=Takami|title=Neuroprotective Effects of the Green Tea Components Theanine and Catechins|journal=Biological & Pharmaceutical Bulletin|volume=25|issue=12|year=2002|pages=1513–1518|issn=0918-6158|doi=10.1248/bpb.25.1513}}</ref> Many [[dissociatives|dissociative]] drugs are antagonists of the NMDA glutamate receptor, including [[ketamine]], [[MXE]], [[PCP]] and [[DXM]]. [[Tramadol]] and [[ibogaine]] are dual antagonists of the NMDA glutamate receptor and [[opioid]] receptors.{{citation needed}}  


*'''Negative Allosteric Modulators'''
*'''Negative Allosteric Modulators'''
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[[Category:Neurotransmitter]]
[[Category:Neurotransmitter]]
[[Category:Amino acid]]
[[Category:Gamma-Amino acid]]
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