High-Resolution Proteomics of Native AMPA Receptors

Neuron Featured Article

High-Resolution Proteomics Unravel Architecture and Molecular Diversity of Native AMPA Receptor Complexes

Jochen Schwenk, Nadine Harmel, Aline Brechet, Gerd Zolles, Henrike Berkefeld, Catrin Swantje Müller, Wolfgang Bildl, David Baehrens, Björn Hüber, Akos Kulik, Nikolaj Klöcker, Uwe Schulte, Bernd Fakler

Summary

AMPA-type glutamate receptors (AMPARs) are responsible for a variety of processes in the mammalian brain including fast excitatory neurotransmission, postsynaptic plasticity, or synapse development. Here, with comprehensive and quantitative proteomic analyses, we demonstrate that native AMPARs are macromolecular complexes with a large molecular diversity. This diversity results from coassembly of the known AMPAR subunits, pore-forming GluA and three types of auxiliary proteins, with 21 additional constituents, mostly secreted proteins or transmembrane proteins of different classes. Their integration at distinct abundance and stability establishes the heteromultimeric architecture of native AMPAR complexes: a defined core with a variable periphery resulting in an apparent molecular mass between 0.6 and 1 MDa. The additional constituents change the gating properties of AMPARs and provide links to the protein dynamics fundamental for the complex role of AMPARs in formation and operation of glutamatergic synapses.

Highlights

• AMPARs are multiprotein assemblies with unappreciated complexity and diversity
• AMPARs are assembled from a pool of 34 proteins, 21 are newly identified constituents
• Coassembly of known and novel subunits generates AMPARs with diverse properties
• The proteome of AMPARs provides fundamental links to their complex cell physiology

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