Glutamate
 |
This article is a stub. As such, it may contain incomplete or wrong information. You can help by expanding it. |
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.[1]
Because of its role in synaptic plasticity, glutamate is involved in cognitive functions such as learning and memory.[2]
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 receptors (GluN1-GluN3), and kainate receptors (GluK1-GluK5).[citation needed][3]
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.[1] It also serves as a metabolic precursor for the neurotransmitter GABA, the main inhibitory neurotransmitter.
Chemistry
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)) [4].
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 [5].
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.
Drugs targeting the glutamate system
- 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.[6]. Because of the high expression and excitatory effects, NMDA receptor overactivation can cause seizures. Stronger agonists are therefore often pro-convulsant and neurotoxic [7].
- Positive Allosteric Modulators
A positive allosteric modulator is a substance which indirectly influences the effects of an agonist at a receptor, by binding to a site distinct from that of the agonist binding site. They usually induce a structural change in the receptor structure. Many nootropics and ampakine (a class of compounds known to enhance attention span and alertness) drugs are positive modulators of the AMPA glutamate receptor. These include piracetam, aniracetam and unifiram.
- Antagonists
A glutamate receptor antagonist is a type of receptor drug that inhibits action at glutamate receptors. 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.[8] Many 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
A negative allosteric modulator is a substance which indirectly influences the effects of an inverse agonist at a receptor, by binding to a site distinct from that of the inverse agonist binding site. Usually they induce a structural change in the receptor structure. Antiepileptic drugs are also found in this class.
See also
External links
Literature
- 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.
References
- ↑ 1.0 1.1 Meldrum, Brian S. (2000). "Glutamate as a Neurotransmitter in the Brain: Review of Physiology and Pathology". The Journal of Nutrition. 130 (4): 1007S–1015S. doi:10.1093/jn/130.4.1007S. ISSN 0022-3166.
- ↑ McEntee, William J.; Crook, Thomas H. (1993). "Glutamate: its role in learning, memory, and the aging brain". Psychopharmacology. 111 (4): 391–401. doi:10.1007/BF02253527. ISSN 0033-3158.
- ↑ Collingridge, Graham L.; Olsen, Richard W.; Peters, John; Spedding, Michael (2009). "A nomenclature for ligand-gated ion channels". Neuropharmacology. 56 (1): 2–5. doi:10.1016/j.neuropharm.2008.06.063. ISSN 0028-3908.
- ↑ Kennely P. J. and Rodwell, V. W, Amino Acids & Peptides (2018). In Harper's Illustrated Biochemistry, pp 14-22, LANGE
- ↑ 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.
- ↑ Wakabayashi, Chisato; Numakawa, Tadahiro; Ninomiya, Midori; Chiba, Shuichi; Kunugi, Hiroshi (2011). "Behavioral and molecular evidence for psychotropic effects in l-theanine". Psychopharmacology. 219 (4): 1099–1109. doi:10.1007/s00213-011-2440-z. ISSN 0033-3158.
- ↑ 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.
- ↑ Kakuda, Takami (2002). "Neuroprotective Effects of the Green Tea Components Theanine and Catechins". Biological & Pharmaceutical Bulletin. 25 (12): 1513–1518. doi:10.1248/bpb.25.1513. ISSN 0918-6158.