SLC1A2

SLC1A2
Identifiers
Aliases	SLC1A2 , EAAT2, GLT-1, HBGT, solute carrier family 1 member 2, EIEE41
External IDs	MGI: 101931 HomoloGene: 3075 GeneCards: SLC1A2
Gene location (Human)
Chr.	Chromosome 11 (human) [1]
End	35,420,063 bp [1]
Gene location (Mouse)
Chr.	Chromosome 2 (mouse) [2]
End	102,790,784 bp [2]
RNA expression pattern
	More reference expression data
Gene ontology
Molecular function	• anion transmembrane transporter activity ; • protein binding ; • symporter activity ; • L-glutamate transmembrane transporter activity ; • amino acid transmembrane transporter activity ; • glutamate:sodium symporter activity ; • high-affinity glutamate transmembrane transporter activity ; • metal ion binding ;
Cellular component	• integral component of membrane ; • membrane ; • plasma membrane ; • cell surface ; • axon ; • axolemma ; • integral component of plasma membrane ;
Biological process	• cellular response to extracellular stimulus ; • chemical synaptic transmission ; • positive regulation of glucose import ; • response to amino acid ; • response to light stimulus ; • multicellular organism growth ; • D-aspartate import ; • ion transport ; • nervous system development ; • glutamate secretion ; • telencephalon development ; • anion transmembrane transport ; • adult behavior ; • response to wounding ; • multicellular organism aging ; • response to drug ; • visual behavior ; • protein homotrimerization ; • L-glutamate import across plasma membrane ; • amino acid transport ; • L-glutamate transport ;
	Sources:Amigo / QuickGO
Orthologs
	6506
	20511
	ENSG00000110436
	ENSMUSG00000005089
	P43004
	P43006
	NM_001195728 ; NM_001252652 ; NM_004171
	NM_001077514 ; NM_001077515 ; NM_011393 ; NM_001361018
	NP_001182657 ; NP_001239581 ; NP_004162
	NP_001070982 ; NP_001070983 ; NP_035523 ; NP_001347947
	Wikidata
View/Edit Human	View/Edit Mouse

Last updated February 19, 2019

Excitatory amino acid transporter 2 (EAAT2) also known as solute carrier family 1 member 2 (SLC1A2) and glutamate transporter 1 (GLT-1) is a protein that in humans is encoded by the SLC1A2 gene.^[5]^[6] Alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known.^[6]

Protein biological molecule consisting of chains of amino acid residues

Proteins are large biomolecules, or macromolecules, consisting of one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, providing structure to cells and organisms, and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the nucleotide sequence of their genes, and which usually results in protein folding into a specific three-dimensional structure that determines its activity.

In biology, a gene is a sequence of nucleotides in DNA or RNA that codes for a molecule that has a function. During gene expression, the DNA is first copied into RNA. The RNA can be directly functional or be the intermediate template for a protein that performs a function. The transmission of genes to an organism's offspring is the basis of the inheritance of phenotypic trait. These genes make up different DNA sequences called genotypes. Genotypes along with environmental and developmental factors determine what the phenotypes will be. Most biological traits are under the influence of polygenes as well as gene–environment interactions. Some genetic traits are instantly visible, such as eye color or number of limbs, and some are not, such as blood type, risk for specific diseases, or the thousands of basic biochemical processes that constitute life.

Function

SLC1A2 / EAAT2 is a member of a family of the solute carrier family of proteins. The membrane-bound protein is the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors.^[6] EAAT2 is responsible for over 90% of glutamate reuptake within the brain.^[7]^[8]

The solute carrier (SLC) group of membrane transport proteins include over 400 members organized into 65 families. Most members of the SLC group are located in the cell membrane. The SLC gene nomenclature system was originally proposed by the HUGO Gene Nomenclature Committee (HGNC) and is the basis for the official HGNC names of the genes that encode these transporters. A more general transmembrane transporter classification can be found in TCDB database.

Neurotransmitters are endogenous chemicals that enable neurotransmission. It is a type of chemical messenger which transmits signals across a chemical synapse, such as a neuromuscular junction, from one neuron to another "target" neuron, muscle cell, or gland cell. Neurotransmitters are released from synaptic vesicles in synapses into the synaptic cleft, where they are received by neurotransmitter receptors on the target cells. Many neurotransmitters are synthesized from simple and plentiful precursors such as amino acids, which are readily available from the diet and only require a small number of biosynthetic steps for conversion. Neurotransmitters play a major role in shaping everyday life and functions. Their exact numbers are unknown, but more than 200 chemical messengers have been uniquely identified.

Glutamic acid is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is non-essential in humans, meaning the body can synthesize it. It is also an excitatory neurotransmitter, in fact the most abundant one, in the vertebrate nervous system. It serves as the precursor for the synthesis of the inhibitory gamma-aminobutyric acid (GABA) in GABA-ergic neurons.

This diagram shows the tissue distribution of glutamate transporter 1 (EAAT2) in the brain.^[7]

Clinical significance

Mutations in and decreased expression of this protein are associated with amyotrophic lateral sclerosis (ALS).^[6] The drug riluzole approved for the treatment of ALS upregulates EAAT2.^[9]

Amyotrophic lateral sclerosis (ALS), also known as motor neurone disease (MND) or Lou Gehrig's disease, is a specific disease which causes the death of neurons controlling voluntary muscles. Some also use the term motor neuron disease for a group of conditions of which ALS is the most common. ALS is characterized by stiff muscles, muscle twitching, and gradually worsening weakness due to muscles decreasing in size. It may begin with weakness in the arms or legs, or with difficulty speaking or swallowing. About half of people develop at least mild difficulties with thinking and behavior and most people experience pain. Most eventually lose the ability to walk, use their hands, speak, swallow, and breathe.

Riluzole is a drug used to treat amyotrophic lateral sclerosis. Riluzole delays the onset of ventilator-dependence or tracheostomy in selected patients and may increase survival by approximately two to three months.

Ceftriaxone, an antibiotic, has been shown to induce/enhance the expression of EAAT2, resulting in reduced glutamate activity.^[10] Ceftriaxone has been shown to reduce the development and expression of tolerance to opiates and other drugs of abuse. EAAT2 may possess an important role in drug addiction and tolerance to addictive drugs.^[11]

Ceftriaxone, sold under the trade name Rocephin, is an antibiotic useful for the treatment of a number of bacterial infections. This includes middle ear infections, endocarditis, meningitis, pneumonia, bone and joint infections, intra-abdominal infections, skin infections, urinary tract infections, gonorrhea, and pelvic inflammatory disease. It is also sometimes used before surgery and following a bite wound to try to prevent infection. Ceftriaxone can be given by injection into a vein or into a muscle.

Upregulation of EAAT2 (GLT-1) causes impairment of prepulse inhibition, a sensory gating deficit present in schizophrenics and schizophrenia animal models.^[12]^[13] Some antipsychotics have been shown to reduce the expression of EAAT2.^[14]^[15]

Prepulse inhibition (PPI) is a neurological phenomenon in which a weaker prestimulus (prepulse) inhibits the reaction of an organism to a subsequent strong startling stimulus (pulse). The stimuli are usually acoustic, but tactile stimuli and light stimuli are also used. When prepulse inhibition is high, the corresponding one-time startle response is reduced.

Sensory gating describes neurological processes of filtering out redundant or unnecessary stimuli in the brain from all possible environmental stimuli. Also referred to as gating or filtering, sensory gating prevents an overload of irrelevant information in the higher cortical centers of the brain. The pulvinar nuclei of the thalamus play a major role in attention, and filter out unnecessary information. Although sensory gating is largely automatic, it also occurs within the context of attentional processes. Though the term sensory gating has been used interchangeably with sensorimotor gating, the two are distinct constructs.

Interactions

SLC1A2 has been shown to interact with JUB.^[16]

As a drug target

EAAT2/GLT-1, being the most abundant subtype of glutamate transporter in the CNS, plays a key role in regulation of glutamate neurotransmission. Dysfunction of EAAT2 has been correlated with various pathologies such as traumatic brain injury, stroke, Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, among others. Therefore, activators of the function or enhancers of the expression of EAAT2/GLT-1 could serve as a potential therapy for these conditions. Translational activators of EAAT2/GLT-1, such as ceftriaxone and LDN/OSU-0212320, have been described to have significant protective effects in animal models of ALS and epilepsy. In addition, pharmacological activators of the activity of EAAT2/GLT-1 have been explored for decades and are currently emerging as promising tools for neuroprotection, having potential advantages over expression activators.^[17]

Neurotransmission, is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron, and bind to and react with the receptors on the dendrites of another neuron. A similar process occurs in retrograde neurotransmission, where the dendrites of the postsynaptic neuron release retrograde neurotransmitters that signal through receptors that are located on the axon terminal of the presynaptic neuron, mainly at GABAergic and glutamatergic synapses.

DL-TBOA, WAY-213613, and dihydrokainic acid are known inhibitors of the protein, and function as excitotoxins. They can be considered a novel class of nerve agent toxins, inducing toxic levels of glutamate through transport inhibition in a manner analogous to the effect of sarin on acetylcholine transporters. Antidotes for such a poisoning have never been formally tested for efficacy and are not readily available for medical use.^[18]

Addiction to certain addictive drugs (e.g., cocaine, heroin, alcohol, and nicotine) is correlated with a persistent reduction in the expression of EAAT2 in the nucleus accumbens (NAcc);^[19] the reduced expression of EAAT2 in this region is implicated in addictive drug-seeking behavior.^[19] In particular, the long-term dysregulation of glutamate neurotransmission in the NAcc of addicts is associated with an increase in vulnerability to relapse after re-exposure to the addictive drug or its associated drug cues.^[19] Drugs which help to normalize the expression of EAAT2 in this region, such as N-acetylcysteine, have been proposed as an adjunct therapy for the treatment of addiction to cocaine, nicotine, alcohol, and other drugs.^[19]

Related Research Articles

Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal or glial cell after it has performed its function of transmitting a neural impulse.

Glia, also called glial cells or neuroglia, are non-neuronal cells in the central nervous system and the peripheral nervous system. They maintain homeostasis, form myelin, and provide support and protection for neurons. In the central nervous system, glial cells include oligodendrocytes, astrocytes, ependymal cells, and microglia, and in the peripheral nervous system glial cells include Schwann cells and satellite cells. They have four main functions: (1) to surround neurons and hold them in place; (2) to supply nutrients and oxygen to neurons; (3) to insulate one neuron from another; (4) to destroy pathogens and remove dead neurons. They also play a role in neurotransmission and synaptic connections, and in physiological processes like breathing. While glia were thought to outnumber neurons by a ratio of 10:1, a recent study provides evidence for a ratio of less than 1:1.

A membrane transport protein is a membrane protein involved in the movement of ions, small molecules, or macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembrane proteins; that is they exist permanently within and span the membrane across which they transport substances. The proteins may assist in the movement of substances by facilitated diffusion or active transport. The two main types of proteins involved in such transport are broadly categorized as either channels or carriers. The solute carriers and atypical SLCs are secondary active or facilitative transporters in humans.

Astrocytes, also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. The proportion of astrocytes in the brain is not well defined. Depending on the counting technique used, studies have found that the astrocyte proportion varies by region and ranges from 20% to 40% of all glia. They perform many functions, including biochemical support of endothelial cells that form the blood–brain barrier, provision of nutrients to the nervous tissue, maintenance of extracellular ion balance, and a role in the repair and scarring process of the brain and spinal cord following traumatic injuries.

Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body's most prominent neurotransmitter, the brain's main excitatory neurotransmitter, and also the precursor for GABA, the brain's main inhibitory neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.

Glutamate transporters are a family of neurotransmitter transporter proteins that move glutamate – the principal excitatory neurotransmitter – across a membrane. The family of glutamate transporters is composed of two primary subclasses: the excitatory amino acid transporter (EAAT) family and vesicular glutamate transporter (VGLUT) family. In the brain, EAATs remove glutamate from the synaptic cleft and extrasynaptic sites via glutamate reuptake into glial cells and neurons, while VGLUTs move glutamate from the cell cytoplasm into synaptic vesicles. Glutamate transporters also transport aspartate and are present in virtually all peripheral tissues, including the heart, liver, testes, and bone. They exhibit stereoselectivity for L-glutamate but transport both L-aspartate and D-aspartate.

Excitatory amino-acid transporter 5 (EAAT5) is a protein that in humans is encoded by the SLC1A7 gene.

Excitatory amino-acid transporter 4 (EAAT4) is a protein that in humans is encoded by the SLC1A6 gene.

Neurotransmitter transporters are a class of membrane transport proteins that span the cellular membranes of neurons. Their primary function is to carry neurotransmitters across these membranes and to direct their further transport to specific intracellular locations. There are more than twenty types of neurotransmitter transporters.

Solute carrier family 1, member 3, also known as SLC1A3, is a protein that, in humans, is encoded by the SLC1A3 gene. SLC1A3 is also often called the GLutamate ASpartate Transporter (GLAST) or Excitatory Amino Acid Transporter 1 (EAAT1).

A neurotransmitter sodium symporter (NSS) (TC# 2.A.22) is type of neurotransmitter transporter that catalyzes the uptake of a variety of neurotransmitters, amino acids, osmolytes and related nitrogenous substances by a solute:Na⁺ symport mechanism. The NSS family is a member of the APC superfamily. Its constituents have been found in bacteria, archaea and eukaryotes.

Glutamate ionotropic receptor AMPA type subunit 2 is a protein that in humans is encoded by the GRIA2 gene.

SLC1A1, also known as excitatory amino-acid transporter 3 (EAAT3), is a protein that in humans is encoded by the SLC1A1 gene.

Cystine/glutamate transporter is an antiporter that in humans is encoded by the SLC7A11 gene.

In biochemistry, the glutamate-glutamine cycle is a sequence of events by which an adequate supply of the neurotransmitter glutamate is maintained in the central nervous system. Neurons are unable to synthesize either the neurotransmitter glutamate or γ-aminobutyric acid (GABA) from glucose. Discoveries of glutamine and glutamate pools within intercellular compartments led to suggestions of the glutamate-glutamine cycle working between neurons and astrocytes. The glutamate/GABA-glutamine cycle is a metabolic pathway that describes the release of glutamate or GABA from neurons which are then taken up into astrocytes. In return, astrocytes release glutamine to be taken up into neurons for use as a precursor to the synthesis of glutamate or GABA.

WAY-213,613 is a drug which acts as a reuptake inhibitor for the glutamate transporter subtype EAAT₂, selective over other glutamate transporter subtypes and highly selective over metabotropic and ionotropic glutamate receptors. It is used in scientific research into the function of the glutamate transporters.

Dicarboxylic aminoaciduria is a rare form of aminoaciduria which is an autosomal recessive disorder of urinary glutamate and aspartate due to genetic errors related to transport of these amino acids. Mutations resulting in a lack of expression of the SLC1A1 gene, a member of the solute carrier family, are found to cause development of dicarboxylic aminoaciduria in humans. SLC1A1 encodes for EAAT3 which is found in the neurons, intestine, kidney, lung, and heart. EAAT3 is part of a family of high affinity glutamate transporters which transport both glutamate and aspartate across the plasma membrane.

An excitatory amino acid reuptake inhibitor (EAARI) is a type of drug which inhibits the reuptake of the excitatory neurotransmitters glutamate and aspartate by blocking one or more of the excitatory amino acid transporters (EAATs).

In neuroscience, glutamate refers to the anion of glutamic acid in its role as a neurotransmitter: a chemical that nerve cells use to send signals to other cells. It is by a wide margin the most abundant excitatory neurotransmitter in the vertebrate nervous system. It is used by every major excitatory function in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain. It also serves as the primary neurotransmitter for some localized brain regions, such as cerebellum granule cells.

References

1 2 3 GRCh38: Ensembl release 89: ENSG00000110436 - Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000005089 - Ensembl, May 2017
↑ "Human PubMed Reference:".
↑ "Mouse PubMed Reference:".
↑ Pines G, Danbolt NC, Bjørås M, Zhang Y, Bendahan A, Eide L, Koepsell H, Storm-Mathisen J, Seeberg E, Kanner BI (Dec 1992). "Cloning and expression of a rat brain L-glutamate transporter". Nature. 360 (6403): 464–7. doi:10.1038/360464a0. PMID 1448170.
1 2 3 4 "Entrez Gene: SLC1A2 solute carrier family 1 (glial high affinity glutamate transporter), member 2".
1 2 Rao P, Yallapu MM, Sari Y, Fisher PB, Kumar S (July 2015). "Designing Novel Nanoformulations Targeting Glutamate Transporter Excitatory Amino Acid Transporter 2: Implications in Treating Drug Addiction". J. Pers. Nanomed. 1 (1): 3–9. PMC 4666545  . 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].
↑ 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.
↑ Carbone M, Duty S, Rattray M (2012). "Riluzole elevates GLT-1 activity and levels in striatal astrocytes". Neurochem. Int. 60 (1): 31–8. doi:10.1016/j.neuint.2011.10.017. PMC 3430367  . PMID 22080156.
↑ Lee SG, Su ZZ, Emdad L, Gupta P, Sarkar D, Borjabad A, Volsky DJ, Fisher PB (May 2008). "Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes". J. Biol. Chem. 283 (19): 13116–23. doi:10.1074/jbc.M707697200. PMC 2442320  . PMID 18326497.
↑ Reissner KJ, Kalivas PW (2010). "Using glutamate homeostasis as a target for treating addictive disorders". Behav Pharmacol. 21 (5-6): 514–22. doi:10.1097/FBP.0b013e32833d41b2. PMC 2932669  . PMID 20634691.
↑ Bellesi M, Melone M, Gubbini A, Battistacci S, Conti F (2009). "GLT-1 upregulation impairs prepulse inhibition of the startle reflex in adult rats". Glia. 57 (7): 703–13. doi:10.1002/glia.20798. PMID 18985735.
↑ Bellesi M, Conti F (2010). "The mGluR2/3 agonist LY379268 blocks the effects of GLT-1 upregulation on prepulse inhibition of the startle reflex in adult rats". Neuropsychopharmacology. 35 (6): 1253–60. doi:10.1038/npp.2009.225. PMC 3055342  . PMID 20072121.
↑ Schmitt A, Zink M, Petroianu G, May B, Braus DF, Henn FA (2003). "Decreased gene expression of glial and neuronal glutamate transporters after chronic antipsychotic treatment in rat brain". Neurosci. Lett. 347 (2): 81–4. doi:10.1016/S0304-3940(03)00653-0. PMID 12873733.
↑ Vallejo-Illarramendi A, Torres-Ramos M, Melone M, Conti F, Matute C (2005). "Clozapine reduces GLT-1 expression and glutamate uptake in astrocyte cultures". Glia. 50 (3): 276–9. doi:10.1002/glia.20172. PMID 15739191.
↑ Marie H, Billups D, Bedford FK, Dumoulin A, Goyal RK, Longmore GD, Moss SJ, Attwell D (February 2002). "The amino terminus of the glial glutamate transporter GLT-1 interacts with the LIM protein Ajuba". Mol. Cell. Neurosci. 19 (2): 152–64. doi:10.1006/mcne.2001.1066. PMID 11860269.
↑ Fontana AC (June 20, 2015). "Current approaches to enhance glutamate transporter function and expression". Journal of Neurochemistry. 134: 982–1007. doi:10.1111/jnc.13200. PMID 26096891.
↑ KEIKO SHIMAMOTO, BRUNO LEBRUN, YOSHIMI YASUDA-KAMATANI, MASAHIRO SAKAITANI, YASUSHI SHIGERI, NOBORU YUMOTO, and TERUMI NAKAJIMA. "DL-threo-b-Benzyloxyaspartate, A Potent Blocker of Excitatory Amino Acid Transporters" (PDF). Molecular Pharmacology.
1 2 3 4 McClure EA, Gipson CD, Malcolm RJ, Kalivas PW, Gray KM (2014). "Potential role of N-acetylcysteine in the management of substance use disorders". CNS Drugs. 28 (2): 95–106. doi:10.1007/s40263-014-0142-x. PMC 4009342  . PMID 24442756.