- The AMPA receptor (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) is a subtype of ionotropic glutamate receptor that mediates fast excitatory synaptic transmission in the central nervous system.
- It is named after its selective agonist AMPA, a synthetic analog of glutamate. AMPA receptors are tetrameric assemblies composed of various combinations of four subunits: GluA1 (GRIA1), GluA2 (GRIA2), GluA3 (GRIA3), and GluA4 (GRIA4). Each subunit has a modular architecture consisting of an extracellular amino-terminal domain (ATD), a ligand-binding domain (LBD) that binds glutamate, a transmembrane domain (TMD) that forms the ion channel pore, and an intracellular carboxy-terminal domain (CTD) involved in anchoring and signaling. The subunit composition critically influences the receptor’s biophysical and pharmacological properties, such as ion selectivity and conductance.
- Functionally, AMPA receptors are responsible for most of the rapid excitatory neurotransmission in the brain.
- Upon glutamate binding, the receptor undergoes a conformational change that opens its ion channel pore, allowing the influx of Na⁺ and, in certain subunit configurations, Ca²⁺, while promoting K⁺ efflux.
- The presence or absence of the GluA2 subunit is the main determinant of calcium permeability: GluA2-containing AMPA receptors are generally impermeable to Ca²⁺ due to RNA editing of the Q/R site in the pore region, whereas GluA2-lacking receptors are calcium-permeable, contributing to synaptic plasticity and excitotoxicity.
- The rapid kinetics of AMPA receptor opening and closing make them ideal for mediating the fast component of excitatory postsynaptic currents (EPSCs) in glutamatergic synapses.
- AMPA receptors play a central role in synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), which underlie learning and memory. Changes in the number, subunit composition, and phosphorylation state of AMPA receptors at postsynaptic sites can modify synaptic strength. This trafficking is tightly regulated by scaffolding proteins such as PSD-95, TARPs (transmembrane AMPA receptor regulatory proteins), and other auxiliary subunits, which influence receptor localization, stability, and gating properties. During LTP, for example, an increased insertion of GluA1-containing AMPA receptors into the postsynaptic membrane strengthens synaptic transmission.
- Clinically, dysregulation of AMPA receptor expression or function has been implicated in numerous neurological and psychiatric disorders, including epilepsy, ischemic brain injury, amyotrophic lateral sclerosis (ALS), schizophrenia, and Alzheimer’s disease. In excitotoxic conditions, overactivation of calcium-permeable AMPA receptors leads to excessive Ca²⁺ influx, triggering cascades that result in neuronal injury and death.
- Pharmacologically, AMPA receptor antagonists such as perampanel are used as anticonvulsants, while positive allosteric modulators (ampakines) are being investigated for their potential to enhance cognition by prolonging receptor open times.
