Glutamate transporter
Encyclopedia
Excitatory amino-acid transporters (EAAT), formerly known as Glutamate transporters, belong to the family of neurotransmitter transporter
s. They serve to terminate the excitatory neurotransmitter signal by removal (uptake) of glutamate
from the neuronal synapse
into Glia cells.
In details, the EAATs are membrane-bound pumps that resemble ion channel
s. These transporters play the important role of regulating concentrations of glutamate in the extracellular space, keeping it at low levels. 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.
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 cascade
s. The activity of glutamate transporters also allows glutamate to be recycled for repeated release.
Glutamate transporters are also present in many other tissues such as bone and testes
.
of sodium
ions (the EAATs) and those that are not (VGluTs). Some sodium independent transporters such as the cystine-glutamate antiporter (xCT) are localised to plasma membrane of cells whilst others there 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). Some Na+-dependent transporters have also been called 'high-affinity transporters', though their glutamate affinity actually varies widely.
mitochondria
also possess mechanisms for taking up glutamate that are quite distinct from membrane glutamate transporters.
, SLC1A1
, ). Subtypes EAAT1-2 are found in membranes of glial cells (astrocyte
s, microglia
, and oligodendrocyte
s) as well as in endothelial cells, whereas EAAT3-4 is located on neurons. Finally, EAAT5 is only found in the retina where it is principally localised to photoreceptors and bipolar neurons in the retina. In rodents, the orthologs for EAAT1-3 are named GLAST
, GLT1, and EAAC1, respectively, whereas the acronyms EAAT4 and EAAT5 are conserved.
When glutamate is taken up into Glia cells by the EAATs, it is not reused directly but converted to glutamine and stored in vesicles. Subsequently these vesicles are released from Glia cells and glutamine transported back into the presynaptic neuron, converted back into glutamate, and store into vesicles by action of the VGLUTs. This process is named the glutamate-glutamine cycle
.
The Glia transporters - in particularly the various splice variants of GLT-1 (EAAT2) - play the largest role (90%) in regulating extracellular glutamate concentration.
, SLC17A6, and SLC17A8
respectively) and the novel glutamate/aspartate transporter sialin. These transporters pack the neurotransmitter into synaptic vesicle
s 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. Also unlike EAATs, they do not appear to transport aspartate.
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 receptor
s.
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. Also, degeneration of motor neuron
s in the disease amyotrophic lateral sclerosis
has been linked to loss of EAAT2 from patients' brain
s and spinal cord
s.
Neurotransmitter transporter
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...
s. They serve to terminate the excitatory neurotransmitter signal by removal (uptake) of glutamate
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...
from the neuronal synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
into Glia cells.
In details, the EAATs are membrane-bound pumps that resemble ion channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s. These transporters play the important role of regulating concentrations of glutamate in the extracellular space, keeping it at low levels. After glutamate is released as the result of an action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
, glutamate transporters quickly remove it from the extracellular space to keep its levels low, thereby terminating the synaptic transmission.
Without the activity of glutamate transporters, glutamate would build up and kill cells in a process called excitotoxicity
Excitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
, in which excessive amounts of glutamate acts as a toxin to neurons by triggering a number of biochemical cascade
Biochemical cascade
A biochemical cascade is a series of chemical reactions in which the products of one reaction are consumed in the next reaction. There are several important biochemical cascade reactions in biochemistry, including the enzymatic cascades, such as the coagulation cascade and the complement system,...
s. The activity of glutamate transporters also allows glutamate to be recycled for repeated release.
Glutamate transporters are also present in many other tissues such as bone and testes
Testicle
The testicle is the male gonad in animals. Like the ovaries to which they are homologous, testes are components of both the reproductive system and the endocrine system...
.
Classes
There are two classes of glutamate transporters, those that are dependent on an electrochemical gradientElectrochemical gradient
An electrochemical gradient is a spatial variation of both electrical potential and chemical concentration across a membrane; that is, a combination of the membrane potential and the pH gradient...
of sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
ions (the EAATs) and those that are not (VGluTs). Some sodium independent transporters such as the cystine-glutamate antiporter (xCT) are localised to plasma membrane of cells whilst others there 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). Some Na+-dependent transporters have also been called 'high-affinity transporters', though their glutamate affinity actually varies widely.
mitochondria
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
also possess mechanisms for taking up glutamate that are quite distinct from membrane glutamate transporters.
EAATs
In humans (as well as in rodents), five subtypes have been identified and named EAAT1-5 (SLC1A3, SLC1A2SLC1A2
Excitatory amino-acid transporter 2 also known as solute carrier family 1 member 2 is a protein that in humans is encoded by the SLC1A2 gene...
, SLC1A1
SLC1A1
Excitatory amino-acid transporter 3 is a protein that in humans is encoded by the SLC1A1 gene.-Further reading:...
, ). Subtypes EAAT1-2 are found in membranes of glial cells (astrocyte
Astrocyte
Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
s, microglia
Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...
, and oligodendrocyte
Oligodendrocyte
Oligodendrocytes , or oligodendroglia , are a type of brain cell. They are a variety of neuroglia. Their main function is the insulation of axons in the central nervous system of some vertebrates...
s) as well as in endothelial cells, whereas EAAT3-4 is located on neurons. Finally, EAAT5 is only found in the retina where it is principally localised to photoreceptors and bipolar neurons in the retina. In rodents, the orthologs for EAAT1-3 are named GLAST
Glutamate aspartate transporter
Solute carrier family 1 , member 3, also known as SLC1A3,is a protein that, in humans, is encoded by the SLC1A3 gene...
, GLT1, and EAAC1, respectively, whereas the acronyms EAAT4 and EAAT5 are conserved.
When glutamate is taken up into Glia cells by the EAATs, it is not reused directly but converted to glutamine and stored in vesicles. Subsequently these vesicles are released from Glia cells and glutamine transported back into the presynaptic neuron, converted back into glutamate, and store into vesicles by action of the VGLUTs. This process is named the glutamate-glutamine cycle
Glutamate-glutamine cycle
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....
.
The Glia transporters - in particularly the various splice variants of GLT-1 (EAAT2) - play the largest role (90%) in regulating extracellular glutamate concentration.
| protein | gene | tissue distribution |
|---|---|---|
| EAAT1 | SLC1A3 | glial and endothelial cells |
| EAAT2 | SLC1A2 SLC1A2 Excitatory amino-acid transporter 2 also known as solute carrier family 1 member 2 is a protein that in humans is encoded by the SLC1A2 gene... |
glial and endothelial cells |
| EAAT3 | SLC1A1 SLC1A1 Excitatory amino-acid transporter 3 is a protein that in humans is encoded by the SLC1A1 gene.-Further reading:... |
neurons |
| EAAT4 | SLC1A6 | neurons |
| EAAT5 | SLC1A7 | retina |
| VGLUT1 | SLC17A7 SLC17A7 Vesicular glutamate transporter 1 is a protein that in humans is encoded by the SLC17A7 gene.-Further reading:... |
neurons |
| VGLUT2 | SLC17A6 | neurons |
| VGLUT3 | SLC17A8 SLC17A8 Solute carrier family 17 member 8 also known as the vesicular glutamate transporter 3 is a protein that in humans is encoded by the SLC17A8 gene.- Function :This gene encodes a vesicular glutamate transporter... |
neurons |
VGluTs
Four types of vesicular glutamate transporters are known, VGLUTs 1–3 (SLC17A7SLC17A7
Vesicular glutamate transporter 1 is a protein that in humans is encoded by the SLC17A7 gene.-Further reading:...
, SLC17A6, and SLC17A8
SLC17A8
Solute carrier family 17 member 8 also known as the vesicular glutamate transporter 3 is a protein that in humans is encoded by the SLC17A8 gene.- Function :This gene encodes a vesicular glutamate transporter...
respectively) and the novel glutamate/aspartate transporter sialin. These transporters pack the neurotransmitter into synaptic vesicle
Synaptic vesicle
In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell...
s so that they can be released into the synapse. VGLUTs are dependent on the proton
Proton
The proton is a subatomic particle with the symbol or and a positive electric charge of 1 elementary charge. One or more protons are present in the nucleus of each atom, along with neutrons. The number of protons in each atom is its atomic number....
gradient that exists in the secretory system
Secretion
Secretion is the process of elaborating, releasing, and oozing chemicals, or a secreted chemical substance from a cell or gland. In contrast to excretion, the substance may have a certain function, rather than being a waste product...
(vesicles
Synaptic vesicle
In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell...
being more acidic than the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
). 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.
Pathology
Overactivity of glutamate transporters may result in inadequate synaptic glutamate and may be involved in schizophreniaSchizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
and other mental illnesses.
During injury processes such as ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
and traumatic brain injury
Traumatic brain injury
Traumatic brain injury , also known as intracranial injury, occurs when an external force traumatically injures the brain. TBI can be classified based on severity, mechanism , or other features...
, 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
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
to power ATPase
ATPase
ATPases are a class of enzymes that catalyze the decomposition of adenosine triphosphate into adenosine diphosphate and a free phosphate ion. This dephosphorylation reaction releases energy, which the enzyme harnesses to drive other chemical reactions that would not otherwise occur...
pumps, resulting in the loss of the electrochemical ion gradient
Electrochemical gradient
An electrochemical gradient is a spatial variation of both electrical potential and chemical concentration across a membrane; that is, a combination of the membrane potential and the pH 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 receptor
Glutamate receptor
Glutamate receptors are synaptic receptors located primarily on the membranes of neuronal cells. Glutamate is one of the 20 amino acids used to assemble proteins and as a result is abundant in many areas of the body, but it also functions as a neurotransmitter and is particularly abundant in the...
s.
Loss of the Na+-dependent glutamate transporter EAAT2 is suspected to be associated with neurodegenerative diseases such as Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, Huntington's disease
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
, and ALS–parkinsonism dementia complex. Also, degeneration of motor neuron
Motor neuron
In vertebrates, the term motor neuron classically applies to neurons located in the central nervous system that project their axons outside the CNS and directly or indirectly control muscles...
s in the disease amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
has been linked to loss of EAAT2 from patients' brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
s and spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
s.
See also
- Dopamine transporterDopamine transporterThe dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
s - Norepinephrine transporterNorepinephrine transporterThe norepinephrine transporter , also known as solute carrier family 6 member 2 , is a protein that in humans is encoded by the SLC6A2 gene....
s - Serotonin transporterSerotonin transporterThe serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
s - NMDA receptorNMDA receptorThe NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
s - AMPA receptorAMPA receptorThe α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system . Its name is derived from its ability to be activated by the artificial glutamate analog AMPA...
s - Kainate receptorKainate receptorKainate receptors, or KARs, are non-NMDA ionotropic receptors which respond to the neurotransmitter glutamate. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a drug first isolated from red algae Digenea simplex. KARs are less well...
s - Metabotropic glutamate receptorMetabotropic glutamate receptorThe metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs...
s