AMPA receptor
Overview
The AMPA receptor or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is a type of ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system (CNS). Its name is derived from its ability to be activated by the artificial glutamate analog AMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonist quisqualate and was only later given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the pharmaceutical company Novo Nordisk.
Structure
The AMPA receptor is a tetramer composed of four subunits, each of which is encoded by a separate gene. The subunits are designated as GluR1 (GRIA1), GluR2 (GRIA2), GluR3 (GRIA3), and GluR4 (GRIA4), or alternatively as GluA1, GluA2, GluA3, and GluA4. Each subunit has four membrane-spanning domains (M1–M4), a large extracellular loop between M3 and M4, which includes the ligand-binding domain, and the N-terminus and a large C-terminus both located intracellularly.
Function
AMPA receptors are responsible for the majority of fast excitatory synaptic transmission in the brain. When an action potential arrives at the synapse, it causes glutamate to be released from the presynaptic cell. Glutamate then binds to the AMPA receptor, causing it to open and allow the flow of sodium (Na+) and potassium (K+) ions. This flow of ions causes a depolarization of the postsynaptic cell and, if the depolarization is strong enough, may trigger an action potential in that cell.
Role in Neurological Disorders
AMPA receptors have been implicated in a number of neurological disorders. Overactivation of AMPA receptors can lead to excitotoxicity, which is thought to be a cause of cell death in stroke and neurodegenerative diseases such as Alzheimer's. Conversely, underactivation of AMPA receptors, leading to insufficient excitation, is implicated in conditions such as schizophrenia and depression.
Pharmacology
AMPA receptors are the target of a number of drugs, including competitive and non-competitive antagonists, positive allosteric modulators, and negative allosteric modulators. Competitive antagonists, such as NBQX and perampanel, bind to the same site as the neurotransmitter glutamate and prevent it from activating the receptor. Non-competitive antagonists, such as GYKI 52466, bind to a different site and inhibit the receptor's function. Positive allosteric modulators, such as aniracetam and CX717, enhance the receptor's response to glutamate. Negative allosteric modulators, such as IEM-1460 and IEM-1925, reduce the receptor's response to glutamate.