The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors

Jeffrey N. Savas, Luís F. Ribeiro, Keimpe D. Wierda, Rebecca Wright, Laura A. DeNardo-Wilke, Heather C. Rice, Ingrid Chamma, Yi Zhi Wang, Roland Zemla, Mathieu Lavallée-Adam, Kristel M. Vennekens, Matthew L. O'Sullivan, Joseph K. Antonios, Elizabeth A. Hall, Olivier Thoumine, Alan D. Attie, John R. Yates*, Anirvan Ghosh, Joris de Wit

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

The formation, function, and plasticity of synapses require dynamic changes in synaptic receptor composition. Here, we identify the sorting receptor SorCS1 as a key regulator of synaptic receptor trafficking. Four independent proteomic analyses identify the synaptic adhesion molecule neurexin and the AMPA glutamate receptor (AMPAR) as major proteins sorted by SorCS1. SorCS1 localizes to early and recycling endosomes and regulates neurexin and AMPAR surface trafficking. Surface proteome analysis of SorCS1-deficient neurons shows decreased surface levels of these, and additional, receptors. Quantitative in vivo analysis of SorCS1-knockout synaptic proteomes identifies SorCS1 as a global trafficking regulator and reveals decreased levels of receptors regulating adhesion and neurotransmission, including neurexins and AMPARs. Consequently, glutamatergic transmission at SorCS1-deficient synapses is reduced due to impaired AMPAR surface expression. SORCS1 mutations have been associated with autism and Alzheimer disease, suggesting that perturbed receptor trafficking contributes to synaptic-composition and -function defects underlying synaptopathies. The formation, function, and plasticity of synapses require changes in receptor composition. Savas et al. identify the sorting receptor SorCS1 as a major regulator of receptor trafficking and show that SorCS1 maintains synaptic levels of key adhesion and neurotransmitter receptors.

Original languageEnglish (US)
Pages (from-to)764-780
Number of pages17
JournalNeuron
Volume87
Issue number4
DOIs
StatePublished - Aug 19 2015

ASJC Scopus subject areas

  • Neuroscience(all)

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