Excitatory amino acid transporter

Excitatory amino acid transporters (EAATs), also known as glutamate transporters, belong to the family of neurotransmitter transporters. Glutamate is the principal excitatory neurotransmitter in the vertebrate brain. EAATs serve to terminate the excitatory signal by removal (uptake) of glutamate from the neuronal synaptic cleft into neuroglia and neurons.

The EAATs are membrane-bound secondary transporters that superficially resemble ion channels. These transporters play the important role of regulating concentrations of glutamate in the extracellular space by transporting it along with other ions across cellular membranes. 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 cascades. The activity of glutamate transporters also allows glutamate to be recycled for repeated release.

Glutamate transporters also transport aspartate and are present in virtually all peripheral tissues including bone, heart, liver, and testes. They exhibit stereoselectivity for L-glutamate but transport both L- and D-aspartate.

Classes

There are two general classes of glutamate transporters, those that are dependent on an electrochemical gradient of sodium ions (the EAATs) and those that are not (VGLUTs and xCT). The cystine-glutamate antiporter (xCT) is localised to the plasma membrane of cells whilst vesicular glutamate transporters (VGLUTs) are found in the membrane of glutamate-containing synaptic vesicles. Na⁺-dependent EAATs are also dependent on transmembrane K⁺ and H⁺concentration gradients, and so are also known as 'sodium and potassium coupled glutamate transporters'. Na⁺-dependent transporters have also been called 'high-affinity glutamate transporters', though their glutamate affinity actually varies widely.

Mitochondria 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, SLC1A2, SLC1A1, SLC1A6, SLC1A7). Subtypes EAAT1-2 are found in membranes of glial cells (astrocytes, microglia, and oligodendrocytes). However, low levels of EAAT2 are also found in the axon-terminals of hippocampal CA3 pyramidal cells. The EAAT3-4 subtypes are exclusively neuronal, and are expressed in axon terminals, cell bodies, and dendrites., Finally, EAAT5 is only found in the retina where it is principally localized to photoreceptors and bipolar neurons in the retina. The glial transporters, especiall EAAT2, play the largest role (90%) in regulating extracellular glutamate concentration.

When glutamate is taken up into glial cells by the EAATs, it is converted to glutamine and subsequently transported back into the presynaptic neuron, converted back into glutamate, and taken up into synaptic vesicles by action of the VGLUTs. This process is named the glutamate-glutamine cycle.

protein	gene	tissue distribution
EAAT1	SLC1A3	astroglial cells
EAAT2	SLC1A2	astroglial cells; low levels in some neurons
EAAT3	SLC1A1	all neurons - dendrites and axon-terminals
EAAT4	SLC1A6	neurons
EAAT5	SLC1A7	retina
VGLUT1	SLC17A7	neurons
VGLUT2	SLC17A6	neurons
VGLUT3	SLC17A8	neurons

VGLUTs

Three types of vesicular glutamate transporters are known, VGLUTs 1–3 (SLC17A7, SLC17A6, and SLC17A8 respectively) and the novel glutamate/aspartate transporter sialin. These transporters pack the neurotransmitter into synaptic vesicles 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.

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.

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 neurons in the disease amyotrophic lateral sclerosis has been linked to loss of EAAT2 from patients' brains and spinal cords.

See also

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

External links

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