Glutamate aspartate transporter

SLC1A3
Identifiers
Aliases	SLC1A3 , EA6, EAAT1, GLAST, GLAST1, solute carrier family 1 member 3
External IDs	OMIM: 600111 MGI: 99917 HomoloGene: 20882 GeneCards: SLC1A3
Gene location (Human)
Chr.	Chromosome 5 (human) [1]
End	36,688,334 bp [1]
Gene location (Mouse)
Chr.	Chromosome 15 (mouse) [2]
End	8,710,764 bp [2]
RNA expression pattern
	More reference expression data
Gene ontology
Molecular function	• amino acid binding ; • symporter activity ; • glutamate binding ; • L-glutamate transmembrane transporter activity ; • amino acid transmembrane transporter activity ; • high-affinity glutamate transmembrane transporter activity ; • acidic amino acid transmembrane transporter activity ; • glutamate:sodium symporter activity ; • metal ion binding ;
Cellular component	• integral component of membrane ; • cell projection ; • membrane ; • plasma membrane ; • cell surface ; • neuronal cell body ; • neuron projection ; • cell periphery ; • integral component of plasma membrane ;
Biological process	• chemical synaptic transmission ; • gamma-aminobutyric acid biosynthetic process ; • glutamate biosynthetic process ; • neuromuscular process controlling balance ; • response to light stimulus ; • cell morphogenesis involved in neuron differentiation ; • cranial nerve development ; • response to antibiotic ; • ion transport ; • sensory perception of sound ; • glutamate secretion ; • auditory behavior ; • neurotransmitter uptake ; • response to wounding ; • positive regulation of synaptic transmission ; • glutamate metabolic process ; • response to drug ; • L-glutamate import ; • amino acid transport ; • D-aspartate import ; • potassium ion transmembrane transport ; • L-glutamate import across plasma membrane ; • L-aspartate import across plasma membrane ; • chloride transmembrane transport ; • L-glutamate transport ;
	Sources:Amigo / QuickGO
Orthologs
	6507
	20512
	ENSG00000079215
	ENSMUSG00000005360
	P43003
	P56564
	NM_001166695 ; NM_001166696 ; NM_001289939 ; NM_001289940 ; NM_004172 Contents Mechanism ; Tissue distribution ; Clinical significance ; Pharmacology ; References ; Further reading ; External links ;
	NM_148938
	NP_001160167 ; NP_001160168 ; NP_001276868 ; NP_001276869 ; NP_004163
	NP_683740
	Wikidata
View/Edit Human	View/Edit Mouse

Last updated April 04, 2019

Solute carrier family 1 (glial high-affinity glutamate transporter), member 3, also known as SLC1A3, is a protein that, in humans, is encoded by the SLC1A3 gene.^[5] SLC1A3 is also often called the GLutamate ASpartate Transporter (GLAST) or Excitatory Amino Acid Transporter 1 (EAAT1) .

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.

GLAST is predominantly expressed in the plasma membrane, allowing it to remove glutamate from the extracellular space.^[6] It has also been localized in the inner mitochondrial membrane as part of the malate-aspartate shuttle.^[7]

The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space.

The malate-aspartate shuttle is a biochemical system for translocating electrons produced during glycolysis across the semipermeable inner membrane of the mitochondrion for oxidative phosphorylation in eukaryotes. These electrons enter the electron transport chain of the mitochondria via reduction equivalents to generate ATP. The shuttle system is required because the mitochondrial inner membrane is impermeable to NADH, the primary reducing equivalent of the electron transport chain. To circumvent this, malate carries the reducing equivalents across the membrane.

Mechanism

GLAST functions in vivo as a homotrimer.^[8] GLAST mediates the transport of glutamic and aspartic acid with the cotransport of three Na⁺ and one H⁺ cations and counter transport of one K⁺ cation. This co-transport coupling (or symport) allows the transport of glutamate into cells against a concentration gradient.^[9]

A homotrimer is a protein which is composed of three identical units of polypeptide.

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.

Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Similar to all other amino acids it contains an amino group and a carboxylic acid. Its α-amino group is in the protonated –NH⁺
₃ form under physiological conditions, while its α-carboxylic acid group is deprotonated −COO⁻ under physiological conditions. Aspartic acid has an acidic side chain (CH₂COOH) which reacts with other amino acids, enzymes and proteins in the body. Under physiological conditions (pH 7.4) in proteins the side chain usually occurs as the negatively charged aspartate form, −COO⁻. It is a non-essential amino acid in humans, meaning the body can synthesize it as needed. It is encoded by all the codons GAU and GAC.

"Diagram Illustrating the Malate-Aspartate Shuttle Pathway". (Glutamate aspartate transporter labeled at bottom center.)

Expression of SLC1A3 in the Bergmann glia fibers. Mouse brain at 7th postnatal day, sagittal section; GENSAT database.

Tissue distribution

GLAST is expressed throughout the CNS,^[10] and is highly expressed in astrocytes and Bergmann glia in the cerebellum.^[11]^[12] In the retina, GLAST is expressed in Muller cells.^[13] GLAST is also expressed in a number of other tissues including cardiac myocytes.^[7]

The central nervous system (CNS) is the part of the nervous system consisting of the brain and spinal cord. The CNS is so named because it integrates the received information and coordinates and influences the activity of all parts of the bodies of bilaterally symmetric animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish—and it contains the majority of the nervous system. Many consider the retina and the optic nerve, as well as the olfactory nerves and olfactory epithelium as parts of the CNS, synapsing directly on brain tissue without intermediate ganglia. As such, the olfactory epithelium is the only central nervous tissue in direct contact with the environment, which opens up for therapeutic treatments. The CNS is contained within the dorsal body cavity, with the brain housed in the cranial cavity and the spinal cord in the spinal canal. In vertebrates, the brain is protected by the skull, while the spinal cord is protected by the vertebrae. The brain and spinal cord are both enclosed in the meninges. Within the CNS, the interneuronal space is filled with a large amount of supporting non-nervous cells called neuroglial cells.

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.

Cerebellum region of the brain that coordinates motor functions and muscle tone

The cerebellum is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebellum plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language as well as in regulating fear and pleasure responses, but its movement-related functions are the most solidly established. The human cerebellum does not initiate movement, but contributes to coordination, precision, and accurate timing: it receives input from sensory systems of the spinal cord and from other parts of the brain, and integrates these inputs to fine-tune motor activity. Cerebellar damage produces disorders in fine movement, equilibrium, posture, and motor learning in humans.

Clinical significance

It is associated with type 6 episodic_ataxia.^[14]

Pharmacology

DL-threo-beta-benzyloxyaspartate (TBOA) is an inhibitor of the excitatory amino acid transporters.^[15]

Selective inhibitors for GLAST have recently been discovered based on 25 combinations of substitutions at the 4 and 7 positions of 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitril.^[16]

Related Research Articles

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.

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.

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.

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. Alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known.

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

Neutral amino acid transporter B(0) is a protein that in humans is encoded by the SLC1A5 gene.

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

Sodium-coupled neutral amino acid transporter 2 is a protein that in humans is encoded by the SLC38A2 gene.

Neutral amino acid transporter A is a protein that in humans is encoded by the SLC1A4 gene.

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.

Solute carrier family 17 member 8 (SLC17A8) also known as the vesicular glutamate transporter 3 (VGluT3) is a protein that in humans is encoded by the SLC17A8 gene.

Monocarboxylate transporter 10, also known as aromatic amino acid transporter 1 and T-type amino acid transporter 1 (TAT1) and solute carrier family 16 member 10 (SLC16A10), is a protein that in humans is encoded by the SLC16A10 gene. SLC16A10 is a member of the solute carrier family.

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.

Solute carrier family 25 member 22 is a protein that in humans is encoded by the SLC25A22 gene. This gene encodes a mitochondrial glutamate carrier. Mutations in this gene are associated with early infantile epileptic encephalopathy. Expression of this gene is increased in colorectal tumor cells.

References

1 2 3 GRCh38: Ensembl release 89: ENSG00000079215 - Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000005360 - Ensembl, May 2017
↑ "Human PubMed Reference:".
↑ "Mouse PubMed Reference:".
↑ "Entrez Gene: SLC1A3 solute carrier family 1 (glial high affinity glutamate transporter), member 3".
↑ Lehre KP, Levy LM, Ottersen OP, Storm-Mathisen J, Danbolt NC (March 1995). "Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations". The Journal of Neuroscience. 15 (3 Pt 1): 1835–53. PMID 7891138.
1 2 Ralphe JC, Segar JL, Schutte BC, Scholz TD (2004). "Localization and function of the brain excitatory amino acid transporter type 1 in cardiac mitochondria". J. Mol. Cell. Cardiol. 37 (1): 33–41. doi:10.1016/j.yjmcc.2004.04.008. PMID 15242733.
↑ Gendreau S, Voswinkel S, Torres-Salazar D, Lang N, Heidtmann H, Detro-Dassen S, Schmalzing G, Hidalgo P, Fahlke C (Sep 17, 2004). "A trimeric quaternary structure is conserved in bacterial and human glutamate transporters". The Journal of Biological Chemistry. 279 (38): 39505–12. doi:10.1074/jbc.M408038200. PMID 15265858.
↑ Kanai Y, Hediger MA (2004). "The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects". Pflügers Arch. 447 (5): 469–79. doi:10.1007/s00424-003-1146-4. PMID 14530974.
↑ Danbolt NC (September 2001). "Glutamate uptake". Prog. Neurobiol. 65 (1): 1–105. doi:10.1016/S0301-0082(00)00067-8. PMID 11369436.
↑ Storck T, Schulte S, Hofmann K, Stoffel W (1992). "Structure, expression, and functional analysis of a Na(+)-dependent glutamate/aspartate transporter from rat brain". Proc. Natl. Acad. Sci. U.S.A. 89 (22): 10955–9. doi:10.1073/pnas.89.22.10955. PMC 50461  . PMID 1279699.
↑ Rothstein JD, Martin L, Levey AI, Dykes-Hoberg M, Jin L, Wu D, Nash N, Kuncl RW (1994). "Localization of neuronal and glial glutamate transporters". Neuron. 13 (3): 713–25. doi:10.1016/0896-6273(94)90038-8. PMID 7917301.
↑ Rauen T, Taylor WR, Kuhlbrodt K, Wiessner M (1998). "High-affinity glutamate transporters in the rat retina: a major role of the glial glutamate transporter GLAST-1 in transmitter clearance". Cell Tissue Res. 291 (1): 19–31. doi:10.1007/s004410050976. PMID 9394040.
↑ Jen JC, Wan J, Palos TP, Howard BD, Baloh RW (2005). "Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures". Neurology. 65 (4): 529–34. doi:10.1212/01.WNL.0000172638.58172.5a. PMID 16116111.
↑ Shimamoto K, Lebrun B, Yasuda-Kamatani Y, Sakaitani M, Shigeri Y, Yumoto N, Nakajima T (February 1998). "DL-threo-beta-benzyloxyaspartate, a potent blocker of excitatory amino acid transporters". Molecular Pharmacology. 53 (2): 195–201. PMID 9463476.
↑ Jensen AA, Erichsen MN, Nielsen CW, Stensbøl TB, Kehler J, Bunch L (Feb 26, 2009). "Discovery of the first selective inhibitor of excitatory amino acid transporter subtype 1". Journal of Medicinal Chemistry. 52 (4): 912–5. doi:10.1021/jm8013458. PMID 19161278.

External links

Glutamate Aspartate Transporter 1 at the US National Library of Medicine Medical Subject Headings (MeSH)

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[refGRCh38Ensembl-1] 1 2 3 GRCh38: Ensembl release 89: ENSG00000079215 - Ensembl, May 2017

[refGRCm38Ensembl-2] 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000005360 - Ensembl, May 2017

[3] "Human PubMed Reference:".

[4] "Mouse PubMed Reference:".

[entrez-5] "Entrez Gene: SLC1A3 solute carrier family 1 (glial high affinity glutamate transporter), member 3".

[6] Lehre KP, Levy LM, Ottersen OP, Storm-Mathisen J, Danbolt NC (March 1995). "Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations". The Journal of Neuroscience. 15 (3 Pt 1): 1835–53. PMID 7891138.

[pmid15242733-7] 1 2 Ralphe JC, Segar JL, Schutte BC, Scholz TD (2004). "Localization and function of the brain excitatory amino acid transporter type 1 in cardiac mitochondria". J. Mol. Cell. Cardiol. 37 (1): 33–41. doi:10.1016/j.yjmcc.2004.04.008. PMID 15242733.

[8] Gendreau S, Voswinkel S, Torres-Salazar D, Lang N, Heidtmann H, Detro-Dassen S, Schmalzing G, Hidalgo P, Fahlke C (Sep 17, 2004). "A trimeric quaternary structure is conserved in bacterial and human glutamate transporters". The Journal of Biological Chemistry. 279 (38): 39505–12. doi:10.1074/jbc.M408038200. PMID 15265858.

[pmid14530974-9] Kanai Y, Hediger MA (2004). "The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects". Pflügers Arch. 447 (5): 469–79. doi:10.1007/s00424-003-1146-4. PMID 14530974.

[pmid11369436-10] Danbolt NC (September 2001). "Glutamate uptake". Prog. Neurobiol. 65 (1): 1–105. doi:10.1016/S0301-0082(00)00067-8. PMID 11369436.

[pmid1279699-11] Storck T, Schulte S, Hofmann K, Stoffel W (1992). "Structure, expression, and functional analysis of a Na(+)-dependent glutamate/aspartate transporter from rat brain". Proc. Natl. Acad. Sci. U.S.A. 89 (22): 10955–9. doi:10.1073/pnas.89.22.10955. PMC 50461  . PMID 1279699.

[pmid7917301-12] Rothstein JD, Martin L, Levey AI, Dykes-Hoberg M, Jin L, Wu D, Nash N, Kuncl RW (1994). "Localization of neuronal and glial glutamate transporters". Neuron. 13 (3): 713–25. doi:10.1016/0896-6273(94)90038-8. PMID 7917301.

[pmid9394040-13] Rauen T, Taylor WR, Kuhlbrodt K, Wiessner M (1998). "High-affinity glutamate transporters in the rat retina: a major role of the glial glutamate transporter GLAST-1 in transmitter clearance". Cell Tissue Res. 291 (1): 19–31. doi:10.1007/s004410050976. PMID 9394040.

[pmid16116111-14] Jen JC, Wan J, Palos TP, Howard BD, Baloh RW (2005). "Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures". Neurology. 65 (4): 529–34. doi:10.1212/01.WNL.0000172638.58172.5a. PMID 16116111.

[15] Shimamoto K, Lebrun B, Yasuda-Kamatani Y, Sakaitani M, Shigeri Y, Yumoto N, Nakajima T (February 1998). "DL-threo-beta-benzyloxyaspartate, a potent blocker of excitatory amino acid transporters". Molecular Pharmacology. 53 (2): 195–201. PMID 9463476.

[16] Jensen AA, Erichsen MN, Nielsen CW, Stensbøl TB, Kehler J, Bunch L (Feb 26, 2009). "Discovery of the first selective inhibitor of excitatory amino acid transporter subtype 1". Journal of Medicinal Chemistry. 52 (4): 912–5. doi:10.1021/jm8013458. PMID 19161278.