Glutamate transporter

Glutamate transporters, also known as VGLUT, are neurotransmitter transporters that exist in the membranes of neurons and glial cells to remove excess amounts of the neurotransmitters glutamate and aspartate from the synapse. Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS), so glutamate transporters are required in the CNS to modulate its functioning. Since these excitatory amino acids cannot diffuse across the blood brain barrier, they require active transport, which is accomplished by glutamate transporters.cite book | author = Agranoff, Bernard W.; Siegel, George J. | title = Basic neurochemistry: molecular, cellular, and medical aspects | publisher = Lippincott-Raven | location = Philadelphia | year = 1999 | pages = | isbn = 0-397-51820-X | oclc = | doi = ] However, most glutamate is locally synthesised by glial cells.cite journal | author = Pow DV, Robinson SR | title = Glutamate in some retinal neurons is derived solely from glia | journal = Neuroscience | volume = 60 | issue = 2 | pages = 355–66 | year = 1994 | pmid = 7915410 | doi = 10.1016/0306-4522(94)90249-6 | issn = ]

Glutamate transporters are also present in many other tissues such as bone and testes.

Glutamate transporters are proteinaceous, membrane-bound pumps that resemble ion channels.cite book | author = Ganel R, Rothstein JD | editor = Monyer, Hannah; Gabriel A. Adelmann; Jonas, Peter | title = Ionotropic glutamate receptors in the CNS | publisher = Springer | location = Berlin | year = 1999 | pages = 472-493 | chapter = Chapter 15, Glutamate transporter dysfunction and neuronal death | isbn = 3-540-66120-4 | oclc = | doi = ] These transporters play the important role of regulating concentrations of glutamate in the extracellular space, keeping it at low levels.cite journal | author = Han BC, Koh SB, Lee EY, Seong YH | title = Regional difference of glutamate-induced swelling in cultured rat brain astrocytes | journal = Life Sci. | volume = 76 | issue = 5 | pages = 573–83 | year = 2004 | pmid = 15556169 | doi = 10.1016/j.lfs.2004.07.016 | issn = ] 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.cite journal | author = Shigeri Y, Seal RP, Shimamoto K | title = Molecular pharmacology of glutamate transporters, EAATs and VGLUTs | journal = Brain Res. Brain Res. Rev. | volume = 45 | issue = 3 | pages = 250–65 | year = 2004 | pmid = 15210307 | doi = 10.1016/j.brainresrev.2004.04.004 | issn = ]

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.cite journal | author = Zou JY, Crews FT | title = TNF alpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: neuroprotection by NF kappa B inhibition | journal = Brain Res. | volume = 1034 | issue = 1-2 | pages = 11–24 | year = 2005 | pmid = 15713255 | doi = 10.1016/j.brainres.2004.11.014 | issn = ]

Locations

These transporters are found in membranes of glial cells (astrocytes, microglia, and oligodendrocytes) as well as in endothelial cells and neurons.cite journal | author = Anderson CM, Swanson RA | title = Astrocyte glutamate transport: review of properties, regulation, and physiological functions | journal = Glia | volume = 32 | issue = 1 | pages = 1–14 | year = 2000 | pmid = 10975906 | doi = 10.1002/1098-1136(200010)32:1 | issn = ] The transporters in glia, particularly the various splice variants of GLT-1 play the largest role in regulating extracellular glutamate concentration.cite journal | author = Shachnai L, Shimamoto K, Kanner BI | title = Sulfhydryl modification of cysteine mutants of a neuronal glutamate transporter reveals an inverse relationship between sodium dependent conformational changes and the glutamate-gated anion conductance | journal = Neuropharmacology | volume = 49 | issue = 6 | pages = 862–71 | year = 2005 | pmid = 16137722 | doi = 10.1016/j.neuropharm.2005.07.005 | issn = ]

Types

There are two types of glutamate transporters, those that are dependent on an electrochemical gradient of sodium ions and those that are not. Some sodium independent transporters such as the cystein-glutamate antiporter are localised to plasma membrane of cells whilst others the are called vesicular transporters. Na⁺-dependent transporters are actually also dependent on K⁺ concentrations, and so are also known as 'sodium and potassium coupled glutamate transporters' or, in humans, 'excitatory amino acid transporters' (EAATs).cite journal | author = Danbolt NC | title = Glutamate uptake | journal = Prog. Neurobiol. | volume = 65 | issue = 1 | pages = 1–105 | year = 2001 | pmid = 11369436 | doi = 10.1016/S0301-0082(00)00067-8 | issn = ] Some Na⁺-dependent transporters have also been called 'high-affinity transporters', though their glutamate affinity actually varies widely.

In humans, there are currently five known types of Na⁺-dependent glutamate transporters, EAATs 1–5 (Gene|SLC1A3, Gene|SLC1A2, Gene|SLC1A1, Gene|SLC1A6, Gene|SLC1A7) and three types of vesicular glutamate transporters, VGLUTs 1–3. (Gene|SLC17A7, Gene|SLC17A6, Gene|SLC17A8) In addition to these transporters, mitochondria also possess mechanisms for taking up glutamate that are quite distinct from membrane glutamate transporters.

Na⁺-dependent transporters

The sodium concentration-dependent types of transporter play a larger role than VGLUTs do in regulating glutamate concentration. These transporters couple the transport of glutamate to the symport and antiport of K⁺ and Na⁺, and hydroxyl ions.cite book | author = Jessell, Thomas M.; Kandel, Eric R.; Schwartz, James H. | title = Principles of neural science | publisher = McGraw-Hill | location = New York | year = 2000 | pages = 287 | isbn = 0-8385-7701-6 | oclc = | doi = ]

In rodents such as rats, the homologs for humans' EAATs 1, 2 and 3 are called GLAST, GLT1, and EAAC1, respectively. EAAT1 and EAAT2 are mainly found in glial cells, EAAT3 and EAAT4 are mainly found in nerve cells and EAAT5 is a form principally localised to photoreceptors and bipolar neurons in the retina.cite journal | author = Pow DV, Barnett NL | title = Developmental expression of excitatory amino acid transporter 5: a photoreceptor and bipolar cell glutamate transporter in rat retina | journal = Neurosci. Lett. | volume = 280 | issue = 1 | pages = 21–4 | year = 2000 | pmid = 10696802 | doi = 10.1016/S0304-3940(99)00988-X | issn = ]

Vesicular transporters

Vesicular glutamate transporters pack the neurotransmitter into synaptic vesicles so that they can be released into the synapse. VGLUTs are dependent on a proton gradient that they create by hydrolysing adenosine triphosphate (ATP). VGLUTs have only between one hundredth and one thousandth the affinity for glutamate that EAATs have. Also unlike EAATs, they do not appear to transport aspartate.

Function

In addition to removing excess glutamate from the synapse and packaging it into vesicles, glutamate transporters also recycle glutamate after it is used as a neurotransmitter. The glutamate is taken up into glia and converted into the amino acid glutamine, which lacks the potentially toxic excitatory effect of glutamate.cite web | url = http://www.benbest.com/science/anatmind/anatmd10.html | title = The Anatomical Basis of Mind | chapter = Chapter 10 -- Brain Neurotransmitters | accessdate = 2007-11-10 | author = Ben Best ]

The glutamine is released from glia and transported back into neurons, converted back into glutamate, packaged into vesicles by VGLUTs, and stored for later release. This process is called the glutamate-glutamine cycle.

Pathology

Overactivity of glutamate transporters may result in inadequate synaptic glutamate and may be involved in schizophrenia and other mental illnesses.

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.cite book | author = Kim AH, Kerchner GA, Choi DW | editor = Marcoux, Frank W. | title = CNS neuroprotection | publisher = Springer | location = Berlin | year = 2002 | pages = 3-36 | chapter = Chapter 1, Blocking Excitotoxicity | isbn = 3-540-42412-1 | oclc = | doi = ]

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.cite journal | author = Yi JH, Hazell AS | title = Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury | journal = Neurochem. Int. | volume = 48 | issue = 5 | pages = 394–403 | year = 2006 | pmid = 16473439 | doi = 10.1016/j.neuint.2005.12.001 | issn = ] Also, degeneration of motor neurons in the disease amyotrophic lateral sclerosis has been linked to loss of EAAT2 from patients' brains and spinal cords.

ee also

*Dopamine transporters
*Norepinephrine transporters
*Serotonin transporters
*NMDA receptors
*AMPA receptors
*Kainate receptors
*Metabotropic glutamate receptors

References

External links

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