 | |
| Clinical data | |
|---|---|
| Other names | GLU (abbreviation), Glutamate, L-(+)-glutamate |
| Physiological data | |
| Sourcetissues | 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 | |
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| CAS Number | |
| PubChemCID | |
| IUPHAR/BPS | |
| ChemSpider | |
| UNII | |
| KEGG | |
Glutamate is an amino acid, and aneurotransmitter (a chemical that nerve cells use to send signals to other cells). It is by a wide margin the most abundant excitatory neurotransmitter in thevertebratenervous 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 thehuman brain. It also serves as the primary neurotransmitter for some localized brain regions, such ascerebellum granule cells.
Biochemical receptors for glutamate fall into three major classes, known asAMPA receptors,NMDA receptors, andmetabotropic glutamate receptors. A fourth class, known askainate receptors, are similar in many respects to AMPA receptors, but much less abundant. Many synapses use multiple types of glutamate receptors. AMPA receptors areionotropic 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 throughsecond messenger systems to create slow, sustained effects on their targets.
Because of its role insynaptic plasticity, glutamate is involved in cognitive functions such aslearning andmemory in the brain.[2] The form of plasticity known aslong-term potentiation takes place at glutamatergic synapses in thehippocampus,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 ofgrowth cones andsynaptogenesis during brain development.
Glutamate is a very major constituent of a wide variety of proteins; consequently it is one of the most abundant amino acids in the human body.[1] Glutamate is formally classified as anon-essential amino acid, because it can be synthesized (in sufficient quantities for health) fromα-ketoglutaric acid, which is produced as part of thecitric acid cycle by a series of reactions whose starting point iscitrate. Glutamate cannot cross theblood–brain barrier unassisted, but it is actively transported out of 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 thecentral nervous system fromglutamine as part of theglutamate–glutamine cycle by the enzymeglutaminase. This can occur in the presynaptic neuron or in neighboring glial cells.
Glutamate itself serves as metabolic precursor for the neurotransmitterGABA, via the action of the enzymeglutamate decarboxylase.
Glutamate exerts its effects by binding to and activatingcell surface receptors. In mammals, four families of glutamate receptors have been identified, known asAMPA receptors,kainate receptors,NMDA receptors, andmetabotropic 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 areG protein-coupled receptors, meaning that they exert their effects via a complexsecond messenger system.
| 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 transporters,EAAT andVGLUT, are found inneuronal andglial membranes. They rapidly remove glutamate from theextracellular 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 viaNMDA receptor channels, leading to neuronal damage and eventual cell death, and is calledexcitotoxicity.[5] The mechanisms ofcell death include
Excitotoxicity due to excessive glutamate release and impaired uptake occurs as part of theischemic cascade and is associated withstroke,[9]autism,[10] some forms ofintellectual disability, and diseases such asamyotrophic lateral sclerosis,lathyrism, andAlzheimer's disease.[9][11] In contrast, decreased glutamate release is observed under conditions of classicalphenylketonuria[12] leading to developmental disruption ofglutamate receptorexpression.[13]
Glutamic acid has been implicated in epilepticseizures. Microinjection of glutamic acid into neurons produces spontaneousdepolarisations around onesecond apart, and this firing pattern is similar to what is known asparoxysmal depolarizing shift in epileptic attacks. This change in the resting membrane potential at seizure foci could cause spontaneous opening ofvoltage-activated calcium channels, leading to glutamic acid release and further depolarization.[citation needed]
Glutamate functions as a neurotransmitter in every type of animal that has a nervous system, includingctenophores (comb jellies), which branched off from other phyla at an early stage in evolution and lack the other neurotransmitters found ubiquitously among animals, includingserotonin andacetylcholine.[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 ofTrichoplax, 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.[17] The β subunits of the receptor respond with very high affinity to glutamate and glycine.[18] Targeting these receptors has been the therapeutic goal ofanthelmintic therapy usingavermectins. Avermectins target the alpha subunit of glutamate-gated chloride channels with high affinity.[19] These receptors have also been described in arthropods, such asDrosophila melanogaster[20] andLepeophtheirus salmonis.[21] 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.
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 ofacetylcholine,norepinephrine, andserotonin as neurotransmitters.[22] The first suggestion that glutamate might function as a transmitter came from T. Hayashi in 1952, who was motivated by the finding that injections of glutamate into thecerebral ventricles of dogs could cause them to have seizures.[22][23]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.[22] 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.[22]
see pages 19 and 20 of Guide Book