The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors
Neuron. 2015-08-01; 87(4): 764-780
DOI: 10.1016/j.neuron.2015.08.007
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1. Neuron. 2015 Aug 19;87(4):764-80. doi: 10.1016/j.neuron.2015.08.007.
The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors.
Savas JN(1), Ribeiro LF(2), Wierda KD(2), Wright R(3), DeNardo-Wilke LA(3), Rice
HC(2), Chamma I(4), Wang YZ(5), Zemla R(6), Lavallée-Adam M(7), Vennekens KM(2),
O’Sullivan ML(3), Antonios JK(3), Hall EA(5), Thoumine O(4), Attie AD(8), Yates
JR 3rd(9), Ghosh A(10), de Wit J(11).
Author information:
(1)Department of Chemical Physiology, The Scripps Research Institute, La Jolla,
CA 92037, USA; Department of Neurology, Feinberg School of Medicine, Northwestern
University, Chicago, IL 60611, USA.
(2)VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human
Genetics, KU Leuven, 3000 Leuven, Belgium.
(3)Neurobiology Section, Division of Biology, University of California, San
Diego, La Jolla, CA 92093, USA.
(4)UMR 5297, Interdisciplinary Institute for Neuroscience, University of Bordeaux
and Centre National de la Recherche Scientifique, 33000 Bordeaux, France.
(5)Department of Neurology, Feinberg School of Medicine, Northwestern University,
Chicago, IL 60611, USA.
(6)School of Medicine, New York University, New York, New York 10016, USA.
(7)Department of Chemical Physiology, The Scripps Research Institute, La Jolla,
CA 92037, USA.
(8)Department of Biochemistry, University of Wisconsin-Madison, Madison, WI
53706, USA.
(9)Department of Chemical Physiology, The Scripps Research Institute, La Jolla,
CA 92037, USA. Electronic address: .
(10)Neurobiology Section, Division of Biology, University of California, San
Diego, La Jolla, CA 92093, USA; Neuroscience Discovery, F. Hoffman-La Roche, 4070
Basel, Switzerland.
(11)VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human
Genetics, KU Leuven, 3000 Leuven, Belgium. Electronic address:
.
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.
Copyright © 2015 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.neuron.2015.08.007
PMCID: PMC4692362
PMID: 26291160 [Indexed for MEDLINE]