The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic glutamate receptor (iGluR) and predominantly sodium ion channel that mediates fast excitatory neurotransmission in the central nervous system (CNS). Its activation by the neurotransmitter glutamate facilitates rapid neuronal communication, essential for various brain functions, including learning and memory. Its name is derived from the ability to be activated by the artificial glutamate analog AMPA. The receptor was initially named the "quisqualate receptor" by Watkins and colleagues after the naturally occurring agonist quisqualate. Later, the receptor was designated as the "AMPA receptor" following the development of the selective agonist AMPA by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen. The GRIA2-encoded AMPA receptor ligand binding core (GluA2 LBD) was the first glutamate receptor ion channel domain to be crystallized.
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ð AMPA receptor in the context of NMDA receptor
The N-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a "coincidence detector" and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.
The NMDA receptor is ionotropic, meaning it is a protein which allows the passage of ions through the cell membrane. The NMDA receptor is so named because the agonist molecule N-methyl-D-aspartate (NMDA) binds selectively to it, and not to other glutamate receptors. Activation of NMDA receptors results in the opening of the ion channel that is nonselective to cations, with a combined reversal potential near 0Â mV. While the opening and closing of the ion channel is primarily gated by ligand binding, the current flow through the ion channel is voltage-dependent. Specifically located on the receptor, extracellular magnesium (Mg) and zinc (Zn) ions can bind and prevent other cations from flowing through the open ion channel. A voltage-dependent flow of predominantly calcium (Ca), sodium (Na), and potassium (K) ions into and out of the cell is made possible by the depolarization of the cell, which displaces and repels the Mg and Zn ions from the pore. Ca flux through NMDA receptors in particular is thought to be critical in synaptic plasticity, a cellular mechanism for learning and memory, due to proteins which bind to and are activated by Ca ions.
AMPA receptor in the context of Excitotoxicity
In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate receptors such as NMDA receptors or AMPA receptors encounter excessive levels of the excitatory neurotransmitter, glutamate, significant neuronal damage might ensue. Different mechanisms might lead to increased extracellular glutamate concentrations, e.g. reduced uptake by glutamate transporters (EAATs), synaptic hyperactivity, or abnormal release from different neural cell types. Excess glutamate allows high levels of calcium ions (Ca) to enter the cell. Ca influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA. In evolved, complex adaptive systems such as biological life it must be understood that mechanisms are rarely, if ever, simplistically direct. For example, NMDA, in subtoxic amounts, can block glutamate toxicity and induce neuronal survival. In addition to abnormally high neurotransmitter concentrations, also elevation of the extracellular potassium concentration, acidification and other mechanisms may contribute to excitotoxicity.
Excitotoxicity may be involved in cancers, spinal cord injury, stroke, traumatic brain injury, hearing loss (through noise overexposure or ototoxicity), and in neurodegenerative diseases of the central nervous system such as multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, alcoholism, alcohol withdrawal or hyperammonemia and especially over-rapid benzodiazepine withdrawal, and also Huntington's disease. Other common conditions that cause excessive glutamate concentrations around neurons are hypoglycemia. Blood sugars are the primary energy source for glutamate removal from inter-synaptic spaces at the NMDA and AMPA receptor site. Persons in excitotoxic shock must never fall into hypoglycemia. Patients should be given 5% glucose (dextrose) IV drip during excitotoxic shock to avoid a dangerous build up of glutamate. When 5% glucose (dextrose) IV drip is not available high levels of fructose are given orally. Treatment is administered during the acute stages of excitotoxic shock along with glutamate receptor antagonists. Dehydration should be avoided as this also contributes to the concentrations of glutamate in the inter-synaptic cleft and "status epilepticus can also be triggered by a build up of glutamate around inter-synaptic neurons."