Glutamate transporter

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] EAATs are antiporters wich carry one molecule of glutamate in along with three Na+ and one H+, while export one K+.[11] EAATs are transmembrane integral proteins which traverse the plasmalemma 8 times.[11]

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[12] (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.[13] The EAAT3-4 subtypes are exclusively neuronal, and are expressed in axon terminals,[8] cell bodies, and dendrites.[9][14] Finally, EAAT5 is only found in the retina where it is principally localized to photoreceptors and bipolar neurons in the retina.[15]

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

VGLUTs

Three types of vesicular glutamate transporters are known, VGLUTs 1–3[17] (SLC17A7, SLC17A6, and SLC17A8 respectively)[3] and the novel glutamate/aspartate transporter sialin.[18] 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.

VGluT3

VGluT3 (Vesicular Glutamate Transporter 3) that is encoded by the SLC17A8 gene is a member of the vesicular glutamate transporter family that transports glutamate into the cells. It is involved in neurological and pain diseases.

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.[19][20][21][22] 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 another two vesicular glutamate transporter, VGluT1 and VGluT2.[23][24]

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 neuropathic pain hypersensivity. In this case, Vesicular glutamate transporter 3 (VGluT3), have been implicated in mechanical hypersensitivity after inflammation, but their role in neuropathic pain still remains under debate.

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.

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.[25]

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.[26] Also, degeneration of motor neurons in the disease amyotrophic lateral sclerosis has been linked to loss of EAAT2 from patients' brains and spinal cords.[26]

Role in addiction

Addiction to any/every drug of abuse tested so far has been correlated with an enduring reduction in the expression of GLT1 (EAAT2) in the nucleus accumbens and is implicated in the drug-seeking behavior expressed nearly universally across all documented addiction syndromes. This long-term dysregulation of glutamate transmission is associated with an increase in vulnerability to both relapse-events after re-exposure to drug-use triggers as well as an overall increase in the likelihood of developing addiction to other reinforcing drugs. Drugs which help to re-stabilize the glutamate system such as N-acetylcysteine are being researched for the treatment of addiction to cocaine, nicotine, and alcohol, with promising preliminary results.[27]

See also

References

  1. 1 2 3 Ganel R, Rothstein JD (1999). "Chapter 15, Glutamate transporter dysfunction and neuronal death". In Monyer, Hannah, Gabriel A. Adelmann, Jonas, Peter. 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.
  3. 1 2 3 4 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 4103010Freely accessible. 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. 1 2 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. 1 2 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 4159050Freely accessible. 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. 1 2 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. 1 2 3 Danbolt NC (2001). "Glutamate uptake". Prog. Neurobiol. 65 (1): 1–105. doi:10.1016/S0301-0082(00)00067-8. PMID 11369436.
  11. 1 2 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
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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 2575331Freely accessible. PMID 18695252.
  19. ↑ Fremeau RT, Burman J, Qureshi T, Tran CH, Proctor J, Johnson J, Zhang H, Sulzer D, Copenhagen DR, Storm-Mathisen J, Reimer RJ, Chaudhry FA, Edwards RH (2002). "The identification of vesicular glutamate transporter 3 suggests novel modes of signaling by glutamate". Proceedings of the National Academy of Sciences of the United States of America. 99 (22): 14488–93. doi:10.1073/pnas.222546799. PMC 137910Freely accessible. PMID 12388773.
  20. ↑ Gras C, Herzog E, Bellenchi GC, Bernard V, Ravassard P, Pohl M, Gasnier B, Giros B, El Mestikawy S (2002). "A third vesicular glutamate transporter expressed by cholinergic and serotoninergic neurons". The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 22 (13): 5442–51. PMID 12097496.
  21. ↑ Schäfer MK, Varoqui H, Defamie N, Weihe E, Erickson JD (2002). "Molecular cloning and functional identification of mouse vesicular glutamate transporter 3 and its expression in subsets of novel excitatory neurons". The Journal of Biological Chemistry. 277 (52): 50734–48. doi:10.1074/jbc.M206738200. PMID 12384506.
  22. ↑ Takamori S, Malherbe P, Broger C, Jahn R (2002). "Molecular cloning and functional characterization of human vesicular glutamate transporter 3". EMBO Reports. 3 (8): 798–803. doi:10.1093/embo-reports/kvf159. PMC 1084213Freely accessible. PMID 12151341.
  23. ↑ Ruel J, Emery S, Nouvian R, Bersot T, Amilhon B, Van Rybroek JM, Rebillard G, Lenoir M, Eybalin M, Delprat B, Sivakumaran TA, Giros B, El Mestikawy S, Moser T, Smith RJ, Lesperance MM, Puel JL (2008). "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice". American Journal of Human Genetics. 83 (2): 278–92. doi:10.1016/j.ajhg.2008.07.008. PMC 2495073Freely accessible. PMID 18674745.
  24. ↑ Seal RP, Akil O, Yi E, Weber CM, Grant L, Yoo J, Clause A, Kandler K, Noebels JL, Glowatzki E, Lustig LR, Edwards RH (2008). "Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3". Neuron. 57 (2): 263–75. doi:10.1016/j.neuron.2007.11.032. PMC 2293283Freely accessible. PMID 18215623.
  25. ↑ Kim AH, Kerchner GA, Choi DW (2002). "Chapter 1, Blocking Excitotoxicity". In Marcoux, Frank W. CNS neuroprotection. Berlin: Springer. pp. 3–36. ISBN 3-540-42412-1.
  26. 1 2 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.
  27. ↑ Erin A. McClure,corresponding author Cassandra D. Gipson, Robert J. Malcolm, Peter W. Kalivas, and Kevin M. Gray. "Potential Role of N-Acetylcysteine in the Management of Substance Use Disorders". CNS Drugs. doi:10.1007/s40263-014-0142-x.

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