The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors

• Published in: Neuron (Cambridge, Mass.) Mass.), 2015-08, Vol.87 (4), p.764-780
• Main Authors: Savas, Jeffrey N., Ribeiro, Luís F., Wierda, Keimpe D., Wright, Rebecca, DeNardo-Wilke, Laura A., Rice, Heather C., Chamma, Ingrid, Wang, Yi-Zhi, Zemla, Roland, Lavallée-Adam, Mathieu, Vennekens, Kristel M., O’Sullivan, Matthew L., Antonios, Joseph K., Hall, Elizabeth A., Thoumine, Olivier, Attie, Alan D., Yates, John R., Ghosh, Anirvan, de Wit, Joris
• Format: Article
• Language: English
• Subjects: Animals; Brain research; Calcium-Binding Proteins; Cells, Cultured; Chromatography; Experiments; Gene Knockdown Techniques; Grants; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins - analysis; Nerve Tissue Proteins - metabolism; Neural Cell Adhesion Molecules - analysis; Neural Cell Adhesion Molecules - metabolism; Neurons; Neurons - chemistry; Neurons - metabolism; Protein Transport - physiology; Proteins; Rats; Rats, Long-Evans; Receptors, AMPA - analysis; Receptors, AMPA - metabolism; Receptors, Cell Surface - analysis; Receptors, Cell Surface - physiology
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2015.08.007

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. •Proteomics identifies neurexins and AMPA receptors as key proteins sorted by SorCS1•SorCS1 regulates surface levels of neurexin and AMPA receptors•SorCS1 maintains synaptic abundance of adhesion proteins and AMPA receptors in vivo•Impaired AMPA receptor trafficking in the absence of SorCS1 reduces synaptic transmission 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.