Excitatory amino-acid transporter

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. 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. 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. 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. EAATs are antiporters which carry one molecule of glutamate in along with three Na+ and one H+, while export one K+. EAATs are transmembrane integral proteins which traverse the plasmalemma 8 times. Mitochondria also possess mechanisms for taking up glutamate that are quite distinct from membrane glutamate transporters. 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. EAAT2 is responsible for over 90% of glutamate reuptake within the central nervous system (CNS). 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. 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. 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. VGluT3 (Vesicular Glutamate Transporter 3) that is encoded by the SLC17A8 gene is a member of the vesicular glutamate transporter family that transports glutamate into the cells. It is involved in neurological and pain diseases.