AMPA Receptor (GluA)
Introduction
Glutamate is the most abundant excitatory neurotransmitter in the central nervous system of vertebrates. Once released into the synaptic cleft, it depolarizes the postsynaptic membrane and activates downstream signaling pathways, thereby propagating excitatory signals. The initial depolarization is primarily mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.
AMPA receptors are ion channels composed of four variable subunits, responsible for rapid excitatory signaling and playing a central role in synaptic plasticity. Their function is regulated at multiple levels by ligands, post-translational modifications, auxiliary proteins, and exogenous regulators. In recent years, high-resolution structural and dynamic imaging techniques have continuously deepened our understanding of receptor conformational changes, subunit specificity, and trans-synaptic localization mechanisms, providing new targets and ideas for the precise treatment of neurological diseases.
Mechanism of AMPA Receptor Action
1. Ligand activation and ion channel
Glutamate binds to the ligand-binding domain (LBD), inducing conformational changes in the transmembrane domain (M1‑M3), allowing rapid influx of Na⁺/K⁺ (and partially Ca²⁺), resulting in postsynaptic depolarization.
2. Rapid desensitization and PRESS mechanism
The receptor briefly opens under high concentrations of glutamate and then rapidly desensitizes. This process is known as pre-equilibrium sensing and signal transduction (PRESS).
3. Auxiliary subunit regulation
Auxiliary proteins such as TARP, GSG1L, and CNIH2/3 regulate receptor function by altering the desensitization time window, channel stability, and ion permeability.
4. Phosphorylation and RNA editing
Kinases such as CaMKII and PKC phosphorylate the C‑terminus, regulating membrane surface stability. RNA editing at Q/R and R/G sites determines Ca²⁺ permeability and desensitization rate.
5. Receptor trafficking and recycling
After assembly in the endoplasmic reticulum, the receptors are transported via the Golgi apparatus and Rab-mediated vesicles to the postsynaptic membrane. Receptors are maintained on the surface through endocytosis and exocytosis cycles, with insertion into the synaptic membrane during LTP and internalization and degradation via lysosomes or proteasomes during LTD.
The synthesis and trafficking pathways of AMPA receptors
References
- Leana-Sandoval G, Kolli AV, Sandoval MA, et al. The VGCC auxiliary subunit α2δ1 is an extracellular GluA1 interactor and regulates LTP, spatial memory, and seizure susceptibility. bioRxiv [Preprint]. 2024 Dec 2:2024.12.02.626379.
- Baranovic J. AMPA receptors in the synapse: Very little space and even less time. Neuropharmacology. 2021 Sep 15;196:108711.
- Liu SJ, Cull-Candy SG (2002) Activity-dependent change in AMPA receptor properties in cerebellar stellate cells. J. Neurosci. 22, 3881--3889.
- Baranovic J, Plested AJ. Auxiliary subunits keep AMPA receptors compact during activation and desensitization. Elife. 2018 Dec 6;7:e40548.
- Henley JM, Wilkinson KA. Synaptic AMPA receptor composition in development, plasticity and disease. Nat Rev Neurosci. 2016 Jun;17(6):337-50.
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