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Three types of vesicular glutamate transporters are known, VGLUTs 1–3<ref name="pmid6130088">{{cite journal |vauthors=Naito S, Ueda T | title = Adenosine triphosphate-dependent uptake of glutamate into protein I-associated synaptic vesicles | journal = J. Biol. Chem. | volume = 258 | issue = 2 | pages = 696–9 |date=January 1983 | pmid = 6130088 | doi = | url = | issn = }}</ref> ([[SLC17A7]], [[SLC17A6]], and [[SLC17A8]] respectively)<ref name="Shigeri"/> and the novel glutamate/aspartate transporter [[sialin]].<ref name="pmid18695252">{{cite journal |vauthors=Miyaji T, Echigo N, Hiasa M, Senoh S, Omote H, Moriyama Y | title = Identification of a vesicular aspartate transporter | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 33 | pages = 11720–4 |date=August 2008 | pmid = 18695252 | pmc = 2575331 | doi = 10.1073/pnas.0804015105 | url = | issn = }}</ref> These transporters pack the neurotransmitter into [[synaptic vesicle]]s so that they can be released into the synapse. VGLUTs are dependent on the [[proton]] gradient that exists in the [[secretion|secretory system]] ([[Synaptic vesicle|vesicles]] being more [[acidic]] than the [[cytosol]]). VGLUTs have only between one hundredth and one thousandth the affinity for glutamate that EAATs have.<ref name="Shigeri"/> Also unlike EAATs, they do not appear to transport aspartate.
Three types of vesicular glutamate transporters are known, VGLUTs 1–3<ref name="pmid6130088">{{cite journal |vauthors=Naito S, Ueda T | title = Adenosine triphosphate-dependent uptake of glutamate into protein I-associated synaptic vesicles | journal = J. Biol. Chem. | volume = 258 | issue = 2 | pages = 696–9 |date=January 1983 | pmid = 6130088 | doi = | url = | issn = }}</ref> ([[SLC17A7]], [[SLC17A6]], and [[SLC17A8]] respectively)<ref name="Shigeri"/> and the novel glutamate/aspartate transporter [[sialin]].<ref name="pmid18695252">{{cite journal |vauthors=Miyaji T, Echigo N, Hiasa M, Senoh S, Omote H, Moriyama Y | title = Identification of a vesicular aspartate transporter | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 33 | pages = 11720–4 |date=August 2008 | pmid = 18695252 | pmc = 2575331 | doi = 10.1073/pnas.0804015105 | url = | issn = }}</ref> These transporters pack the neurotransmitter into [[synaptic vesicle]]s so that they can be released into the synapse. VGLUTs are dependent on the [[proton]] gradient that exists in the [[secretion|secretory system]] ([[Synaptic vesicle|vesicles]] being more [[acidic]] than the [[cytosol]]). VGLUTs have only between one hundredth and one thousandth the affinity for glutamate that EAATs have.<ref name="Shigeri"/> Also unlike EAATs, they do not appear to transport aspartate.


'''Functional backround'''
====Functional backround====
The exocytosis of neurotransmitter into the synaptic cleft underlies the process of information exchange via chemical synapses between neurons in the central nervous system and glutamate is a major excitatory neurotransmitter. As the glutamate for this process is synthesized within neuron, the loading and storage of the amino acid has to precede the exocytotic release. VGluT provides the loading mechanism of glutamate into synaptic vesicles.<ref>Offermanns, Stefan; Rosenthal, W. Encyclopedia of Molecular Pharmacology, Springer Aug 14, 2008 ISBN: 9783540389163.</ref>
The exocytosis of neurotransmitter into the synaptic cleft underlies the process of information exchange via chemical synapses between neurons in the central nervous system and glutamate is a major excitatory neurotransmitter. As the glutamate for this process is synthesized within neuron, the loading and storage of the amino acid has to precede the exocytotic release. VGluT provides the loading mechanism of glutamate into synaptic vesicles.<ref>Offermanns, Stefan; Rosenthal, W. Encyclopedia of Molecular Pharmacology, Springer Aug 14, 2008 ISBN: 9783540389163.</ref>


Revision as of 15:35, 21 October 2016

Glutamate transporters are family of neurotransmitter transporters that contains two subclasses: the excitatory amino acid transporters (EAATs) and the vesicular glutamate transporters (VGLUTs). Glutamate transporters are proteins that move glutamate – the principal excitatory neurotransmitter – across a membrane; in the brain, they normally serve to remove glutamate from the synaptic cleft and extrasynaptic sites via reuptake into neuroglia and neurons as well as move glutamate from the cytoplasm into synaptic vesicles. Glutamate transporters also transport aspartate and are present in virtually all peripheral tissues including bone, heart, liver, and testes. They exhibit stereoselectivity for L-glutamate but transport both L- 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 astroglial cells[5]
EAAT2 SLC1A2 astroglial cells;[6] low levels in some neurons[7]
EAAT3 SLC1A1 all neurons - dendrites and axon-terminals[8][9]
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 electrochemical gradient of sodium ions (the EAATs) and those that are not (VGLUTs and xCT).[10] The cystine-glutamate antiporter (xCT) is localised to the plasma membrane of cells whilst vesicular glutamate transporters (VGLUTs) are found in the membrane of glutamate-containing synaptic vesicles. Na+-dependent EAATs are also dependent on transmembrane K+ and H+concentration gradients, and so are also known as 'sodium and potassium coupled glutamate transporters'. Na+-dependent transporters have also been called 'high-affinity glutamate transporters', though their glutamate affinity actually varies widely.[10]

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 (SLC1A3, SLC1A2, SLC1A1, SLC1A6, SLC1A7). Subtypes EAAT1-2 are found in membranes of glial cells[11] (astrocytes, microglia, and oligodendrocytes). However, low levels of EAAT2 are also found in the axon-terminals of hippocampal CA3 pyramidal cells.[7] EAAT2 is responsible for over 90% of glutamate reuptake within the brain.[12] The EAAT3-4 subtypes are exclusively neuronal, and are expressed in axon terminals,[8] cell bodies, and dendrites.[9][13] Finally, EAAT5 is only found in the retina where it is principally localized to photoreceptors and bipolar neurons in the retina.[14]

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][15] This process is named the glutamate-glutamine cycle.

VGLUTs

The vesicular glutamate transporter (VGluT) is a multitransmembrane domain protein that are present in a vesicular membrane in neurons and is responsible for the uptake of L-glutamate into synaptic vesicles to store them for a later exocytotic release of the excitatory neurotransmitter into a synaptic cleft. Its mechanism of glutamate sequestration is coupled to the electrochemical gradient, especially its electrical component, across the vesicle membrane.

Protein family neurotransmitter vesicular transport originally characterized as dependent cotransporter sodium inorganic phosphate. Sequester excitatory neurotransmitter glutamate from the cytoplasm into the secretory vesicles by luminal proton exchanging it.[16] Amino acid transporters such as glutamate, are considered proteins important in the central nervous system, and involved in the capture after release neurotransmitter in the synaptic cleft to finish in this way their effect and limit the excitability mediated glutamate. These proteins are included in the family of transporters dependent Na / K. Much evidence demonstrates the involvement of several neuronal disorders conveyors, such as epilepsy and cerebral ischemia. Neurotransmitter transporters can be classified into plasma membrane transporters and vesicular membrane transporters.[17] Glutamate is synthesized in the cytoplasm and stored in vesicles by a capture system dependent on an electrochemical gradient.[18] Under normal conditions it is released by exocytosis into the synaptic cleft, where it binds to the glutamate receptors to cause the action potential.[19] Glutamate transporters are responsible for completing the action of glutamate and maintain the extracellular levels below the levels that cause neurotoxicity.[20] Glutamate transporters can be found in neurons and glia. However, the carriers differ in their cellular distribution and regional as well as on their biophysical and pharmacological properties. In glial cells, glutamate becomes glutamine. Then glutamine is transported out of the glial cell and returned to the presynaptic terminal, where it is subsequently converted back into glutamate. Glutamate inside the presynaptic terminal is packaged into synaptic vesicles by the action of a second set of glutamate transporters known as VGlutT (vesicular glutamate transporters), which are present in the membrane of the glutamartegical vesicles. Glutamate transport into synaptic vesicles by VGlutT is caused by transport in the opposite direction of H +, whose electrochemical grandient been established by a H + -ATPase in the vesicle membrane.[21] Three types of vesicular glutamate transporters are known, VGLUTs 1–3[22] (SLC17A7, SLC17A6, and SLC17A8 respectively)[3] and the novel glutamate/aspartate transporter sialin.[23] These transporters pack the neurotransmitter into synaptic vesicles so that they can be released into the synapse. VGLUTs are dependent on the proton gradient that exists in the secretory system (vesicles being more acidic than the cytosol). VGLUTs have only between one hundredth and one thousandth the affinity for glutamate that EAATs have.[3] Also unlike EAATs, they do not appear to transport aspartate.

Functional backround

The exocytosis of neurotransmitter into the synaptic cleft underlies the process of information exchange via chemical synapses between neurons in the central nervous system and glutamate is a major excitatory neurotransmitter. As the glutamate for this process is synthesized within neuron, the loading and storage of the amino acid has to precede the exocytotic release. VGluT provides the loading mechanism of glutamate into synaptic vesicles.[24]

The neurotransmitter cycle When an action potential reaches the presynaptic terminal of a neuron, excitatory neurotransmitter molecules in synaptic vesicles are released into synaptic cleft by exocytosis. Then they bind to receptors on a postsynaptic dendrite, which causes an action potential in the receiving neuron that further induces, modulates, or amplifies the information down a signal cascade. The neurotransmitter is quickly removed from the cleft by the sodio-dependent, high affinity excitatory amino acid transporters (EAATs) residing in the plasma membrane of the presynaptic terminal and of adjacent glial cells. When the glutamate is transported into glial cells, it is converted to glutamine and then transported back to the presynaptic cell (glutamate-glutamine cycle). A vesicular transport system mediates the uptake of recycled or newly synthesized glutamate in the cytosol, hence the proper functioning of VGluT and EAATs maintains a proper intra- and extracellular level of concentration before, during and after neurotransmission.[25]

Mechanism

The mechanism of VGluTs

VGLUT mediates uptake of glutamate by synaptic vesicles prior to its depolarization-triggered, calcium-dependent release from presynaptic terminals. VGluT activity is coupled to a proton electrochemical gradient (∆ ) across the vesicle membrane generated by the vacuolar H⁺-ATPase. Energy produced from the hydrolysis of ATP is used to pump H⁺ into the vesicle, making it more acidic (∆pH) and more positively charged (∆). As opposed to the other vesicular neurotransmitter transport systems, the glutamate transport depend almost exclusively on the electrical component of the gradient (∆). VGLUT has low affinity (= 1-3mM) for glutamate compare to the Na⁺-dependent, excitatory amino acid transporters (EAATs) found of the plasma membrane (= 5 to 50 M) and share little homology. This difference seems to reflect the low tolerance for extracellular glutamate. An abnormally high level of glutamate concentrations are known to be associated with neurotoxicity.[26] The uptake by VGluT shows biphasic dependence on Cl⁻, stimulated when the ion’s concentrations are low but inhibited when high. The exact mechanism involved in the chloride’s role is still unknown, but it is suggested that it works as a counter ion upon the influx of positively charged hydrogen ion mediated by ATPase.[27]

Types: VGluT 1 - 3 Three isoforms of the VGluT have been identified, VGuT1 - 3. Primary structure analysis shows that VGluT1 shares 82.4% homology with VGluT2 and 77.4% with VGluT3, and VGluT2 has 76.3% sequence overlap with VGLUT3. They exhibit a high degree of homology and little differences in the transport properties. However, their differences come from the sites of each transporter subtype’s predominant expression. VGluT1 and VGlut2 show complementary patterns of expression in central nervous system’s glutamatergic neurons. On the other hand VGluT3 is also expressed outside glutamatergic brain and is present where the others are not, such as in GABAergic, cholinergic and monoaminergic neurons. And yet, it seems that in the astrocytes of brain in a developing stage all three isoforms are expressed, VGluT3 expression appearing later than the other two isoforms.

The expression density of the isoforms of VGluT

The VGluT1 (SLC17A7) Also known as the brain-specific Na⁺-dependent phosphate transporter (BNPI), the VGLUT1(accession number NP_064705, GI: 9945322) of homo sapiens consist of a chain of 560 amino acid residues and its molecular weight is about 61.5kD, a theoretical pI of 7.2 and a grand average of hydropathy (GRAVY) of 0.226. It encodes for a transmembrane protein. Owing to its expression pattern, it is the major isoform of the three VGLUTs in cortex, hippocampus, and cerebellar cortex in adult brain, whereas VGLUT2 is temporarily expressed during early postnatal development in these locations.[28] Although VGLUT1 exhibits a high degree of sequence homology with VGLUT2, the C-termini of the former contains two polyproline domains and a phosphorylation consensus sequence in a region of acidic amino acids. [29]. The interaction of a polyproline domain with endophilin, a component of the clathrin-dependent endocytic recycling of synaptic vesicles, recruits VGLUT1 to a fast recycling pathway. [30] Also, VGLUT1 is suggested to be involved in synaptic plasticity. It is reported that the deficiency of VGLUT1 in mice resulted in impaired hippocampal long-term potentiation (LDP) along with a specific deficit in spatial reversal learning, which suggests a functional role of VGLUT1 in synaptic plasticity of the cerebral region.[31]

The VGlut2 is a vesicular transport protein glutamate that is expressed predominantly in the diencephalon and in the lower regions of the brainstem central nervous system.[16] This protein is encoded by the SLC17A6 gene. The function of vesicular glutamate transporter 2 is mediate glutamate uptake into synaptic vesicles in presynaptic nerve terminals of excitatory neuronal cells. It can also mediate transport of inorganic phosphate. It has tissue specificity, as expressed in the adult brain. Expressed in the amygdala, caudate nucleus, cerebral cortex, frontal lobe, hippocampus, medulla, occipital lobe, putamen, spinal cord, substantia nigra, subthalamic nucleus, and thalamus temporal lobe. During the development stage it is expressed in the fetal brain. It is involved in several biological processes such as ion transporter, transmembrane transporter L-glutamate, neurotransmitter transport and transport of sodium ion.[32]

The VGluT3 (SLC17A8) is one of the Vesicular Glutamate Transporter into the cells. Its function is related with neurological and pain diseases. VLGUT3 is expressed in neurons not classically considered glutamatergic. Immunohistochemical and in situ studies indicate VGLUT3 is expressed in GABAergic serotonergic, dopaminergic, and cholinergic neurons as well as astrocytes. Pathology: deafness autosomal dominant.

Neurons using other neurotransmitter than glutamate (such as cholinergic striatal interneurons and 5-HT neurons) express VGluT3. Unlike other subtypes of vesicular glutamate transporters, VGluT3 is expressed preferentially in neurons allegedly using other neurotransmitters than glutamate. Recently, the observation was made that a majority of central 5-HT neurons express the vesicular glutamate transporter VGluT3[33] . The role of this unconventional transporter remains unexplored. As demonstrated in the auditory system,VGluT3 is involved in fast excitatory glutamatergic transmission similarly to the other two subtypes of vesicular glutamate transporter, VGluT1 and VGluT2 [34] . Behavioral and physiological consequences of VGluT3 ablation Serotonergic transmission modulates a wide range of neuronal and physiological processes (anxiety, mood regulation, impulsivity, aggressive behavior, pain perception, sleep–wake cycle, appetite, body temperature, sexual behavior). No significant change in aggression and depression-like behaviors was found in VGluT3 knock-out mice. In contrast, the loss of VGluT3 resulted in a specific anxiety-related phenotype. Indeed, VGluT3-deficient adult mice tested in different conflict-based paradigms exhibited marked neophobia toward anxiogenic contexts or objects.

Sensory nerve fibers differ not only with respect to their sensory modalities and conduction velocities, but also in their relative roles for pain hypersensitivity. It i spresently largely unknown which types of sensory afferents contribute to various forms of neuropathic and inflammatory pain hypersensitivity. Vesicular glutamate transporter 3-positive (VGluT3) primary afferents, for example, have been implicated in mechanical hypersensitivity after inflammation, but their role in neuropathic pain remains under debate.

VGluT3 has extensive somatic throughout development, wich 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.

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.[35]

Loss of the Na+-dependent glutamate transporter EAAT2 is suspected to be associated with neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and ALS–parkinsonism dementia complex.[36] Also, degeneration of motor neurons in the disease amyotrophic lateral sclerosis has been linked to loss of EAAT2 from patients' brains and spinal cords.[36]

See also

References

  1. ^ a b c Ganel R, Rothstein JD (1999). "Chapter 15, Glutamate transporter dysfunction and neuronal death". In Monyer, Hannah, Gabriel A. Adelmann, Jonas, Peter (eds.). Ionotropic glutamate receptors in the CNS. Berlin: Springer. pp. 472–493. ISBN 3-540-66120-4.
  2. ^ Zerangue, N, Kavanaugh, MP (1996). "Flux coupling in a neuronal glutamate transporter". Nature. 383 (6601): 634–37. doi:10.1038/383634a0. PMID 8857541.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ a b c d Shigeri Y, Seal RP, Shimamoto K (2004). "Molecular pharmacology of glutamate transporters, EAATs and VGLUTs". Brain Res. Brain Res. Rev. 45 (3): 250–65. doi:10.1016/j.brainresrev.2004.04.004. PMID 15210307.
  4. ^ Zou JY, Crews FT (2005). "TNF alpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: neuroprotection by NF kappa B inhibition". Brain Res. 1034 (1–2): 11–24. doi:10.1016/j.brainres.2004.11.014. PMID 15713255.
  5. ^ Beardsley PM, Hauser KF (2014). "Glial modulators as potential treatments of psychostimulant abuse". Adv. Pharmacol. 69: 1–69. doi:10.1016/B978-0-12-420118-7.00001-9. PMC 4103010. PMID 24484974.
  6. ^  • Cisneros IE, Ghorpade A (October 2014). "Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes". Neuropharmacology. 85: 499–507. doi:10.1016/j.neuropharm.2014.06.011. 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.
     • Jing L, Li JX (August 2015). "Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction". Eur. J. Pharmacol. 761: 345–352. doi:10.1016/j.ejphar.2015.06.019. PMID 26092759. TAAR1 is largely located in the intracellular compartments both in neurons (Miller, 2011), in glial cells (Cisneros and Ghorpade, 2014) and in peripheral tissues (Grandy, 2007)
  7. ^ a b Furness DN, Dehnes Y, Akhtar AQ, Rossi DJ, Hamann M, Grutle NJ, Gundersen V, Holmseth S, Lehre KP, Ullensvang K, Wojewodzic M, Zhou Y, Attwell D, Danbolt NC (2008). "A quantitative assessment of glutamate uptake into hippocampal synaptic terminals and astrocytes: new insights into a neuronal role for excitatory amino acid transporter 2 (EAAT2)". Neuroscience. 157 (1): 80–94. doi:10.1016/j.neuroscience.2008.08.043. PMID 18805467.
  8. ^ a b Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG (July 2014). "Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons". Neuron. 83 (2): 404–16. doi:10.1016/j.neuron.2014.05.043. PMC 4159050. 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.
  9. ^ a b Holmseth S, Dehnes Y, Huang YH, Follin-Arbelet VV, Grutle NJ, Mylonakou MN, Plachez C, Zhou Y, Furness DN, Bergles DE, Lehre KP, Danbolt NC (2012). "The density of EAAC1 (EAAT3) glutamate transporters expressed by neurons in the mammalian CNS". J Neurosci. 32 (17): 6000–13. doi:10.1523/JNEUROSCI.5347-11.2012. PMID 22539860.
  10. ^ a b c Danbolt NC (2001). "Glutamate uptake". Prog. Neurobiol. 65 (1): 1–105. doi:10.1016/S0301-0082(00)00067-8. PMID 11369436.
  11. ^ Lehre KP, Levy LM, Ottersen OP, Storm-Mathisen J, Danbolt NC (1995). "Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations". J Neurosci. 15 (3): 1835–53. PMID 7891138.
  12. ^ Holmseth S, Scott HA, Real K, Lehre KP, Leergaard TB, Bjaalie JG, Danbolt NC (2009). "The concentrations and distributions of three C-terminal variants of the GLT1 (EAAT2; slc1a2) glutamate transporter protein in rat brain tissue suggest differential regulation". Neuroscience. 162 (4): 1055–71. doi:10.1016/j.neuroscience.2009.03.048. PMID 19328838. 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.
  13. ^ Anderson CM, Swanson RA (2000). "Astrocyte glutamate transport: review of properties, regulation, and physiological functions". Glia. 32 (1): 1–14. doi:10.1002/1098-1136(200010)32:1. PMID 10975906.
  14. ^ Pow DV, Barnett NL (2000). "Developmental expression of excitatory amino acid transporter 5: a photoreceptor and bipolar cell glutamate transporter in rat retina". Neurosci. Lett. 280 (1): 21–4. doi:10.1016/S0304-3940(99)00988-X. PMID 10696802.
  15. ^ Pow DV, Robinson SR (1994). "Glutamate in some retinal neurons is derived solely from glia". Neuroscience. 60 (2): 355–66. doi:10.1016/0306-4522(94)90249-6. PMID 7915410.
  16. ^ a b Biblioteca Virtual en Salud Honduras
  17. ^ Article in Neurociencia; "Structural and functional characteristics of glutamate transporters: their relationship with epilepsy and oxidative stress" (L. Medina-Ceja, H. Guerrero-Cazares)
  18. ^ Balcar VJ. Molecular pharmacology of the Na+ dependent transport of acidic amino acids in the mammalian central nervous system. Biol Pharm Bull 2002; 25: 291-301
  19. ^ Maragakis NJ, Rotstein JD. Glutamate transporters: animal models to neurologic disease. Neurobiol Dis 2004; 15:461-73
  20. ^ Choi DW. Bench to bedside: the glutamate connection. Science 1992; 258:241-3
  21. ^ Berne and Levy. Physiology. Chapter 6 page 97.
  22. ^ Naito S, Ueda T (January 1983). "Adenosine triphosphate-dependent uptake of glutamate into protein I-associated synaptic vesicles". J. Biol. Chem. 258 (2): 696–9. PMID 6130088.
  23. ^ Miyaji T, Echigo N, Hiasa M, Senoh S, Omote H, Moriyama Y (August 2008). "Identification of a vesicular aspartate transporter". Proc. Natl. Acad. Sci. U.S.A. 105 (33): 11720–4. doi:10.1073/pnas.0804015105. PMC 2575331. PMID 18695252.
  24. ^ Offermanns, Stefan; Rosenthal, W. Encyclopedia of Molecular Pharmacology, Springer Aug 14, 2008 ISBN: 9783540389163.
  25. ^ Thompson, Charles; Charles, Thompson; Erin, Davis; Christina, Carrigan; Holly, Cox; Richard, Bridges; John, Gerdes. Inhibitors of the Glutamate Vesicular Transporter (VGLUT) Curr. Med. Chem. 2005 Volume: 12, Issue 18, pages 2041-2056 ISSN: 0929-8673
  26. ^ Thompson, Charles; Charles, Thompson; Erin, Davis; Christina, Carrigan; Holly, Cox; Richard, Bridges; John, Gerdes. Inhibitors of the Glutamate Vesicular Transporter (VGLUT) Curr. Med. Chem. 2005 Volume: 12, Issue 18, pages 2041-2056 ISSN: 0929-8673
  27. ^ Offermanns, Stefan; Rosenthal, W. Encyclopedia of Molecular Pharmacology, Springer Aug 14, 2008 ISBN: 9783540389163
  28. ^ Thompson, Charles; Charles, Thompson; Erin, Davis; Christina, Carrigan; Holly, Cox; Richard, Bridges; John, Gerdes. Inhibitors of the Glutamate Vesicular Transporter (VGLUT) Curr. Med. Chem. 2005 Volume: 12, Issue 18, pages 2041-2056 ISSN: 0929-8673
  29. ^ Santos, Magda S; Foss, Sarah M; Park, C Kevin; Voglmaier, Susan M. Protein interactions of the vesicular glutamate transporter VGLUT1. PLoS One Oct 15, 2014 Vol 9, issue 10, pages e109824. ISSN: 1932-6203
  30. ^ Voglmaier, Susan M; Kam, Kaiwen; Yang, Hua; Fortin, Doris L; Hua, Zhaolin; Nicoll, Roger A; Edwards, Robert H. Distinct endocytic pathways control the rate and extent of synaptic vesicle protein recycling. Neuron, Jul 06, 2006. Volume: 51, issue 1, pages 71-84. ISSN: 0896-6273
  31. ^ Balschun, D; Moechars, D; Callaerts-Vegh, Z; Vermaercke, B; Van Acker, N; Andries, L; D'Hooge, R. Vesicular Glutamate Transporter VGLUT1 Has a Role in Hippocampal Long-Term Potentiation and Spatial Reversal Learning. Cereb. Cortex 2009 Volume 20, Issue 3, pages 684-693. ISSN: 1047-3211
  32. ^ http://www.uniprot.org/uniprot/Q9P2U8
  33. ^ (Fremeau et al.,2002;Gras e tal.,2002;Schäfer et al., 2002; Takamori et al., 2002)
  34. ^ (Ruel et al., 2008; Seal et al.,2008)
  35. ^ Kim AH, Kerchner GA, Choi DW (2002). "Chapter 1, Blocking Excitotoxicity". In Marcoux, Frank W. (ed.). CNS neuroprotection. Berlin: Springer. pp. 3–36. ISBN 3-540-42412-1.
  36. ^ a b Yi JH, Hazell AS (2006). "Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury". Neurochem. Int. 48 (5): 394–403. doi:10.1016/j.neuint.2005.12.001. PMID 16473439.

Bibliography

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VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice. Am J Hum Genet 83:278–292.}}

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