期刊
JOURNAL OF NEUROSCIENCE
卷 30, 期 7, 页码 2728-2740出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5146-09.2010
关键词
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资金
- John Merck Fund, Hellman Foundation
- National Institutes of Health (NIH) [P41004050, 1S10RR20016, GM033050]
- NIH Molecular Biophysics Training Grant [NIH GM08326]
- NIH CMG Training Grant [T32 GM007240-34]
- National Alliance for Research on Schizophrenia and Depression Young Investigator Award
Subunit assembly governs regulation of AMPA receptor (AMPA-R) synaptic delivery and determines biophysical parameters of the ion channel. However, little is known about the molecular pathways of this process. Here, we present single-particle EM three-dimensional structures of dimeric biosynthetic intermediates of the GluA2 subunit of AMPA-Rs. Consistent with the structures of intact tetramers, the N-terminal domains of the biosynthetic intermediates form dimers. Transmembrane domains also dimerize despite the two ligand-binding domains (LBDs) being separated. A significant difference was detected between the dimeric structures of the wild type and the L504Y mutant, a point mutation that blocks receptor trafficking and desensitization. In contrast to the wild type, whose LBD is separated, the LBD of the L504Y mutant was detected as a single density. Our results provide direct structural evidence that separation of the LBD within the intact dimeric subunits is critical for efficient tetramerization in the endoplasmic reticulum and further trafficking of AMPA-Rs. The contribution of stargazin on the subunit assembly of AMPA-R was examined. Our data suggest that stargazin affects AMPA-R trafficking at a later stage of receptor maturation.
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