Molecular Neurobiology

, Volume 42, Issue 3, pp 161-184

First online:

Open Access This content is freely available online to anyone, anywhere at any time.

The Biochemistry, Ultrastructure, and Subunit Assembly Mechanism of AMPA Receptors

  • Terunaga NakagawaAffiliated withDepartment of Chemistry and Biochemistry, University of California, San Diego Email author 


The AMPA-type ionotropic glutamate receptors (AMPA-Rs) are tetrameric ligand-gated ion channels that play crucial roles in synaptic transmission and plasticity. Our knowledge about the ultrastructure and subunit assembly mechanisms of intact AMPA-Rs was very limited. However, the new studies using single particle EM and X-ray crystallography are revealing important insights. For example, the tetrameric crystal structure of the GluA2cryst construct provided the atomic view of the intact receptor. In addition, the single particle EM structures of the subunit assembly intermediates revealed the conformational requirement for the dimer-to-tetramer transition during the maturation of AMPA-Rs. These new data in the field provide new models and interpretations. In the brain, the native AMPA-R complexes contain auxiliary subunits that influence subunit assembly, gating, and trafficking of the AMPA-Rs. Understanding the mechanisms of the auxiliary subunits will become increasingly important to precisely describe the function of AMPA-Rs in the brain. The AMPA-R proteomics studies continuously reveal a previously unexpected degree of molecular heterogeneity of the complex. Because the AMPA-Rs are important drug targets for treating various neurological and psychiatric diseases, it is likely that these new native complexes will require detailed mechanistic analysis in the future. The current ultrastructural data on the receptors and the receptor-expressing stable cell lines that were developed during the course of these studies are useful resources for high throughput drug screening and further drug designing. Moreover, we are getting closer to understanding the precise mechanisms of AMPA-R-mediated synaptic plasticity.


AMPA-type ionotropic glutamate receptors AMPA receptors Glutamate receptors Ionotropic glutamate receptors Biochemistry Ultrastructure Subunit assembly mechanism Subunit assembly Subunit Biosynthesis Biosynthetic intermediates Electron microscopy EM Single particle Single particle EM 3D EM Density map Comparing EM density and X-ray structure Cryo-negative stain single particle EM Cryo-EM Image reconstruction Vesicle trafficking Endoplasmic reticulum Glycosylation X-linked mental retardation Alzheimer’s disease Amyotrophic lateral sclerosis Limbic encephalitis Rasmussen’s encephalitis GluR1 GluR2 GluR3 GluR4 GluA1 GluA2 GluA3 GluA4 Stragazin TARP Cornichon CNIH CKAMP44 SOL-1 Lurcher Membrane biochemistry Synaptic plasticity Synaptic transmission Postsynaptic density Cell biology