Glutamate transporters exist in the membranes of neurons and glial cells to remove excess amounts of the amino acid neurotransmitters glutamate and aspartate from the synapse. Since these excitatory amino acids cannot diffuse across the blood brain barrier, they require active transport, which is accomplished by glutamate transporters (Siegel et al., 1999). Most glutamate is however locally synthesised by glial cells (Pow and Robinson 1994). Glutamate transporters are also present in many other tissues such as bone and in the testis. Glutamate transporters are proteinaceous, membrane-bound pumps that resemble ion channels (Ganel and Rothstein, 1999). Glutamate transporters play the important role of regulating concentrations of glutamate in the extracellular space, keeping it at low levels (Han et al., 2004). 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 (Ganel and Rothstein, 1999; Shigeri et al., 2004). 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 (Zou and Crews, 2005). Drawing of a cell membrane A cell membrane, plasma membrane or plasmalemma is a selectively permeable lipid bilayer coated by proteins which comprises the outer layer of a cell. ... Drawing by Santiago Ramón y Cajal of neurons in the pigeon cerebellum. ... This article or section does not cite its references or sources. ... An amino acid residue is what is left of an amino acid once a molecule of water has been lost (an H+ from the nitrogenous side and an OH- from the carboxylic side) in the formation of a peptide bond. ... Chemical structure of D-Aspartic Acid, a common Amino Acid neurotransmitter. ... Glutamic acid (Glu), also referred to as glutamate (the anion), is one of the 20 proteinogenic amino acids. ... Aspartic acid, also known as aspartate, the name of its anion, is one of the 20 natural proteinogenic amino acids which are the building blocks of proteins. ... Illustration of the major elements in a prototypical synapse. ... This article or section does not cite its references or sources. ... The blood-brain barrier is a physical barrier between the blood vessels in the central nervous system, and the central nervous system itself. ... This article or section does not cite its references or sources. ... A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... Another, unrelated ion channeling process is part of ion implantation. ... A. A schematic view of an idealized action potential illustrates its various phases as the action potential passes a point on a cell membrane. ... Excitotoxicity is the pathological process by which neurons are damaged and killed by the overactivation of excitatory neurotransmitter receptors such as the NMDA receptor and AMPA receptor (which belong to the glutamate receptor family). ... A Biochemical Cascade is a series of chemical reactions in which the products of one reaction are consumed in the next reaction. ...

Locations

These transporters are found in membranes of glial cells (astrocytes, microglia, and oligodendrocytes) as well as in endothelial cells and neurons (Anderson and Swanson, 2005). The transporters in glia, particularly the various splice variants of GLT-1 play the largest role in regulating extracellular glutamate concentration (Shachnai et al., 2005). Astrocytes, also known as astroglia, are characteristic star-shaped glial cells in the brain. ... Microglia are a type of glial cell that act as the immune cells of the Central nervous system (CNS). ... Oligodendrocytes (from Greek literally meaning few tree cells), or oligodendroglia (Greek, few tree glue)[1], are a variety of neuroglia. ... The endothelium is the layer of thin, flat cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. ...

Types

There are two types of glutamate transporters, those that are dependent on an electrochemical gradient of sodium ions and those that are not (Anderson and Swanson, 2005). Some sodium independent transporters such as the cystien-glutamate antiporter are localised to plasmamembrane 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) (Danbolt, 2001). Some Na⁺-dependent transporters have also been called 'high-affinity transporters', though their glutamate affinity actually varies widely (Danbolt, 2001). Electrochemical gradients in cellular biology refers to the electrical and chemical properties across a membrane. ... General Name, Symbol, Number sodium, Na, 11 Chemical series alkali metals Group, Period, Block 1, 3, s Appearance silvery white Atomic mass 22. ...

In humans, there are currently five known types of Na⁺-dependent glutamate transporters, EAATs 1–5, and three types of vesicular glutamate transporters, VGLUTs 1–3 (Shigeri et al., 2004).

In addition to these transporters, mitochondria also possess mechanisms for taking up glutamate that are quite distinct from membrane glutamate transporters (Danbolt, 2001). electron micrograph of a mitochondrion showing its mitochondrial matrix and membranes In cell biology, a mitochondrion (plural mitochondria) (from Greek mitos thread + khondrion granule) is an organelle, variants of which are found in most eukaryotic cells. ...

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 (Kandel et al., 2000). A symporter, also known as a coporter, is an integral membrane protein that is involved in facilitated diffusion. ... An antiporter is an integral membrane protein that is involved in secondary active transport. ... General Name, Symbol, Number potassium, K, 19 Chemical series alkali metals Group, Period, Block 1, 4, s Appearance silvery white Atomic mass 39. ... General Name, Symbol, Number sodium, Na, 11 Chemical series alkali metals Group, Period, Block 1, 3, s Appearance silvery white Atomic mass 22. ... // Hydroxyl group The term hydroxyl group is used to describe the functional group -OH when it is a substituent in an organic compound. ... An ion is an atom, group of atoms, or subatomic particle that normally is electrically neutral and achieve their status as an ion by loss (and addition) of an electron. ...

In rodents such as rats, the homologs for humans' EAATs 1, 2 and 3 are called GLAST, GLT1, and EAAC1, respectively (Shigeri et al., 2004). 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 (Pow and Barnett 2000). In biology, two or more structures are said to be homologous if they are alike because of shared ancestry. ...

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 (Shigeri et al., 2004). Also unlike EAATs, they do not appear to transport aspartate. In a neuron, synaptic vesicles, also called neurotransmitter vesicles, store the various neurotransmitters that are released during calcium-regulated exocytosis at the presynaptic terminal into the synaptic cleft of a synapse. ... Properties [1][2] In physics, the proton (Greek proton = first) is a subatomic particle with an electric charge of one positive fundamental unit (1. ... Adenosine 5-triphosphate (ATP), discovered in 1929 by Karl Lohmann, is a multifunctional nucleotide primarily known in biochemistry as the molecular currency of intracellular energy transfer. ...

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 (Best, 1990). 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 (Pow and Robinson, 1994, Shigeri et al., 2004). This process is called the glutamate-glutamine cycle. Glutamine is one of the 20 amino acids encoded by the standard genetic code. ...

Pathology

Overactivity of glutamate transporters may result in inadequate synaptic glutamate and may be involved in schizophrenia and other mental illnesses (Ganel and Rothstein, 1999).

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 (Kim et al., 2005). In medicine, ischemia (Greek ισχαιμία, isch- is restriction, hema or haema is blood) is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. ... Traumatic brain injury (TBI), traumatic injuries to the brain, also called intracranial injury, or simply head injury, occurs when a sudden trauma causes brain damage. ... Adenosine 5-triphosphate (ATP), discovered in 1929 by Karl Lohmann, is a multifunctional nucleotide primarily known in biochemistry as the molecular currency of intracellular energy transfer. ... ATPases are a class of enzymes that catalyze the decomposition of adenosine triphosphate (ATP) into adenosine diphosphate (ADP) and a free phosphate ion. ... Electrochemical gradients in cellular biology refers to the electrical and chemical properties across a membrane. ... Glutamate is a neurotransmitter in nerve cells which binds to all glutamate receptors located on neuron membranes, and is an example of a transmembrane receptor. ...

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 (Yi and Hazell, 2006). Also, degeneration of motor neurons in the disease amyotrophic lateral sclerosis has been linked to loss of EAAT2 from patients' brains and spinal cords (Yi and Hazell, 2006). Neurodegenerative disease is a condition which affects the brain function. ... In vertebrates, motoneurons (also called motor neurons) are efferent neurons that originate in the spinal cord and synapse with muscle fibers to facilitate muscle contraction and with muscle spindles to modify proprioceptive sensitivity. ... Amyotrophic lateral sclerosis (ALS, sometimes called Lou Gehrig’s disease, Maladie de Charcot or motor neurone disease) is a chronic, progressive, almost invariably fatal neurological disease. ... Comparative brain sizes In animals, the brain, or encephalon (Greek for in the head), is the control center of the central nervous system. ... The Spinal cord nested in the vertebral column. ...

See also

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

The dopamine transporter or DAT is a monoamine transporter that is specific for clearing the neurotransmitter dopamine out of the synaptic cleft and into a glial cell or the presynaptic neuron. ... The norepinephrine transporter or NET is a monoamine transporter that transports the neurotransmitter norepinephrine from the synapse back to its vesicles for storage until later use. ... The serotonin transporter is a monoamine transporter protein. ... The NMDA receptor (NMDAR) is an ionotropic receptor for glutamate (NMDA (N-methyl d-aspartate) is a name of its selective specific agonist). ... The AMPA receptor (AMPAR) is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system. ... Kainate receptors are ionotropic receptors which respond to both glutamate, which is their physiological ligand, or kainate which is a drug first isolated from red alga Digenea simplex. ... Metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor which are active through an indirect metabotropic process. ...

References

• Anderson CM and Swanson RA. 2000. Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia, Volume 32, Issue 1, Pages 1–14.
• Best, B. 1990. Brain Neurotransmitters.
• Danbolt NC. 2001. Glutamate uptake. Progress in Neurobiology. Volume 65, Issue 1, Pages 1−105.
• Ganel R and Rothstein JD. 1999. Glutamate transporter dysfunction and neuronal death. Chapter 15 in Ionotropic glutamate receptors in the CNS. Jonas P and Monyer H, editors. Springer, New York. pp. 472-493.
• Han BC, Koh SB, Lee EY, Seong YH. 2004. Regional difference of glutamate-induced swelling in cultured rat brain astrocytes. Life Sciences, Volume 76, Number 5, Pages 573-583.
• Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science, 4th ed., p.287. McGraw-Hill, New York (2000). ISBN 0-8385-7701-6
• Kim AH, Kerchner GA, and Choi DW. 2002. Blocking Excitotoxicity. Chapter 1 in: CNS Neuroproteciton. Marcoux FW and Choi DW, editors. Springer, New York. Pages 3 - 36.
• Pow DV, Barnett NL. Developmental expression of excitatory amino acid transporter 5: a photoreceptor and bipolar cell glutamate transporter in rat retina. Neurosci Lett. 2000 Feb 11;280(1):21-4.
• Pow DV, Robinson SR. Glutamate in some retinal neurons is derived solely from glia. Neuroscience. 1994 May;60(2):355-66.
• Shachnai L, Shimamoto K, and Kanner BI. 2005. 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. Neuropharmacology, Volume 49, Issue 6, Pages 862-871.
• Shigeri Y, Seal RP, and Shimamoto K. 2004. Molecular pharmacology of glutamate transporters, EAATs and VGLUTs. Brain Research Reviews, Volume 45, Issue 3, Pages 250-265.
• Siegel, G J, Agranoff, BW, Albers RW, Fisher SK, Uhler MD, editors. 1999. Basic Neurochemistry: Molecular, Cellular, and Medical Aspects 6th ed. Philadelphia: Lippincott,Williams & Wilkins.
• Yi J-H and Hazell AS. 2006. Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury. Neurochemistry International, In Press, Corrected Proof, Available online 13 February 2006. Abstract available.
• Zou JY and Crews FT. 2005. TNFαpotentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: neuroprotection by NFκ inhibition. Brain Research, Volume 1034, Issues 1-2, Pages 11-24.