Glutamate transporter
Glutamate transporters are a family of
, and bone. They exhibit stereoselectivity for L-glutamate but transport both L-aspartate and D-aspartate.The EAATs are membrane-bound secondary transporters that superficially resemble ion channels.[1] These transporters play the important role of regulating concentrations of glutamate in the extracellular space by transporting it along with other ions across cellular membranes.[2] After glutamate is released as the result of an action potential, glutamate transporters quickly remove it from the extracellular space to keep its levels low, thereby terminating the synaptic transmission.[1][3]
Without the activity of glutamate transporters, glutamate would build up and kill cells in a process called excitotoxicity, in which excessive amounts of glutamate acts as a toxin to neurons by triggering a number of biochemical cascades. The activity of glutamate transporters also allows glutamate to be recycled for repeated release.[4]
Classes
protein | gene | tissue distribution |
---|---|---|
EAAT1 |
SLC1A3 | astroglia[5]
|
EAAT2 |
SLC1A2 | Mainly astroglia;[6] mediates >90% of CNS glutamate reuptake[7] |
EAAT3 |
SLC1A1 | all neurons – located on |
EAAT4 |
SLC1A6 | neurons |
EAAT5 |
SLC1A7 | retina |
VGLUT1 | SLC17A7 | neurons |
VGLUT2 | SLC17A6 | neurons |
VGLUT3 |
SLC17A8 | neurons |
There are two general classes of glutamate transporters, those that are dependent on an
Mitochondria also possess mechanisms for taking up glutamate that are quite distinct from membrane glutamate transporters.[10]
EAATs
In humans (as well as in rodents), five subtypes have been identified and named EAAT1-5 (
When glutamate is taken up into glial cells by the EAATs, it is converted to glutamine and subsequently transported back into the presynaptic neuron, converted back into glutamate, and taken up into synaptic vesicles by action of the VGLUTs.[3][17] This process is named the glutamate–glutamine cycle.
VGLUTs
Three types of vesicular glutamate transporters are known, VGLUTs 1–3 Also unlike EAATs, they do not appear to transport aspartate.
VGluT3
VGluT3 (Vesicular Glutamate Transporter 3) that is encoded by the
Neurons are able to express VGluT3 when they use a neurotransmitter different to Glutamate, for example in the specific case of central 5-HT neurons.[20][21][22][23] The role of this unconventional transporter (VGluT3) still remains unknown but, at the moment, has been demonstrated that, in auditory system, the VGluT3 is involved in fast excitatory glutamatergic transmission very similar to the other two vesicular glutamate transporters, VGluT1 and VGluT2.[24][25]
There are behavioral and physiological consequences of VGluT3 ablation because it modulates a wide range of neuronal and physiological processes like anxiety, mood regulation, impulsivity, aggressive behavior, pain perception, sleep–wake cycle, appetite, body temperature and sexual behavior. Certainly, no significant change was found in aggression and depression-like behaviors, but in contrast, the loss of VGluT3 resulted in a specific anxiety-related phenotype.
The sensory nerve fibers have different ways to detect the pain hypersensivity throughout their sensory modalities and conduction velocities, but at the moment is still unknown which types of sensory is related to the different forms of inflammatory and
VGluT3 has extensive somatic throughout development, which could be involved in non-synaptic modulation by glutamate in developing retina, and could influence trophic and extra-synaptic neuronal signaling by glutamate in the inner retina.
Molecular Structure of EAATs
Like all glutamate transporters, EAATs are trimers, with each protomer consisting of two domains : the central scaffold domain (Figure 1A, wheat) and the peripheral transport domain (Figure 1A, blue). The transport conformational path is as follows. First, the outward facing conformation occurs (OF, open) which allows the glutamate to bind. Then the HP2 region closes after uptake (OF, closed) and the elevator like movement carries the substrate to the intracellular side of the membrane. It worth nothing that this elevator motion consists of several yet to be categorized/identified conformational changes. After the elevator motion brings the substrate to the IC side of the membrane, EAAT adopts the inward facing (IF, closed) state in which the transport domain is lowered, but the HP2 gate is still closed with the glutamate still bound to the transporter. Lastly, the HP2 gate opens and the glutamate diffuses into the cytoplasm of the cell. [26]
Pathology
Overactivity of glutamate transporters may result in inadequate synaptic glutamate and may be involved in schizophrenia and other mental illnesses.[1]
During injury processes such as ischemia and traumatic brain injury, the action of glutamate transporters may fail, leading to toxic buildup of glutamate. In fact, their activity may also actually be reversed due to inadequate amounts of adenosine triphosphate to power ATPase pumps, resulting in the loss of the electrochemical ion gradient. Since the direction of glutamate transport depends on the ion gradient, these transporters release glutamate instead of removing it, which results in neurotoxicity due to overactivation of glutamate receptors.[27]
Loss of the Na+-dependent glutamate transporter EAAT2 is suspected to be associated with
Addiction to certain addictive drugs (e.g.,
See also
- Dopamine transporters
- Norepinephrine transporters
- Serotonin transporters
- NMDA receptors
- AMPA receptors
- Kainate receptors
- Metabotropic glutamate receptors
References
- ^ ISBN 3-540-66120-4.
- S2CID 4266755.
- ^ S2CID 41057787.
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- PMID 24484974.
- PMID 24950453.
TAAR1 overexpression significantly decreased EAAT-2 levels and glutamate clearance ... METH treatment activated TAAR1 leading to intracellular cAMP in human astrocytes and modulated glutamate clearance abilities. Furthermore, molecular alterations in astrocyte TAAR1 levels correspond to changes in astrocyte EAAT-2 levels and function.
- ^ PMID 26635971.
The glutamate transporter 1 (GLT1)/ excitatory amino acid transporter 2 (EAAT2) is responsible for the reuptake of more than 90% glutamate in the CNS [12–14].
- ^ PMID 25033183.
The dependence of EAAT3 internalization on the DAT also suggests that the two transporters might be internalized together. We found that EAAT3 and DAT are expressed in the same cells, as well as in axons and dendrites. However, the subcellular co-localization of the two neurotransmitter transporters remains to be established definitively by high resolution electron microscopy.
- ^ PMID 22539860.
- ^ S2CID 27347413.
- ^ a b E. R. Kandel, J. H. Schwartz, T. M. Jessell, S. A. Siegelbaum, A. J. Hudpseth, Principles of neural science, 5th ed., The McGraw-Hill Companies, Inc., 2013, p. 304
- ^ S2CID 41615013.
Since then, a family of five high-affinity glutamate transporters has been characterized that is responsible for the precise regulation of glutamate levels at both synaptic and extrasynaptic sites, although the glutamate transporter 1 (GLT1) is responsible for more than 90% of glutamate uptake in the brain.3 The importance of GLT1 is further highlighted by the large number of neuropsychiatric disorders associated with glutamate-induced neurotoxicity. Clarification of nomenclature: The major glial glutamate transporter is referred to as GLT1 in the rodent literature and excitatory amino acid transporter 2 (EAAT2) in the human literature.
- PMID 7891138.
- PMID 18805467.
- PMID 10975906.
- S2CID 13184375.
- S2CID 28256349.
- PMID 6130088.
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- PMID 12097496.
- PMID 12384506.
- PMID 12151341.
- PMID 18674745.
- PMID 18215623.
- S2CID 206090609.
- ISBN 3-540-42412-1.
- ^ S2CID 44719394.
- ^ PMID 24442756.
External links
- Glutamate+Transporter at the U.S. National Library of Medicine Medical Subject Headings (MeSH)