The Biochemistry,Ultrastructure, and Subunit Assembly Mechanism of AMPA Receptors |
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Authors: | Terunaga Nakagawa |
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Institution: | (1) Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA |
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Abstract: | 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. |
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