SAP97 and CASK mediate sorting of NMDA receptors through a previously unknown secretory pathway

• Published in: Nature neuroscience Vol. 12; no. 8; pp. 1011 - 1019
• Main Authors: Lin, Eric I, Green, William N, Specht, Christian G, Jeyifous, Okunola, Waites, Clarissa L, Marshall, John, Garner, Craig C, Schubert, Manja, de Silva, Tharani, Aoki, Chiye, Montgomery, Johanna M, Fujisawa, Sho
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2009; Nature Publishing Group
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animal Genetics and Genomics; Animals; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Biosynthesis; Bodily Secretions - physiology; Cell Compartmentation - physiology; Cell Line; Cells, Cultured; Dendrites - metabolism; Dendrites - ultrastructure; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - ultrastructure; Golgi Apparatus - metabolism; Golgi Apparatus - ultrastructure; Guanylate Kinases - metabolism; Hippocampus - metabolism; Hippocampus - ultrastructure; Humans; Kinases; Kinesin - metabolism; Localization; Membrane Proteins - metabolism; Methyl aspartate; Nerve proteins; Neural receptors; Neurobiology; Neurons - metabolism; Neurons - ultrastructure; Neuroplasticity; Neurosciences; Physiological aspects; Physiology; Plasma; Protein Transport - physiology; Proteins; Rats; Rats, Sprague-Dawley; Receptors, AMPA - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Signal Transduction - physiology; United States; New York; United States > US
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.2362

This study shows that, although AMPA-type glutamate receptors are trafficked to dendrites through the normal Golgi secretory pathway, NMDA receptors bypass the somatic Golgi apparatus and instead move from the endoplasmic reticulum in endoplasmic reticulum–like vesicles to Golgi 'outposts' located in the dendrites. Synaptic plasticity is dependent on the differential sorting, delivery and retention of neurotransmitter receptors, but the mechanisms underlying these processes are poorly understood. We found that differential sorting of glutamate receptor subtypes began in the endoplasmic reticulum of rat hippocampal neurons. As AMPA receptors (AMPARs) were trafficked to the plasma membrane via the conventional somatic Golgi network, NMDA receptors (NMDARs) were diverted from the somatic endoplasmic reticulum into a specialized endoplasmic reticulum subcompartment that bypasses somatic Golgi, merging instead with dendritic Golgi outposts. This endoplasmic reticulum subcompartment was composed of highly mobile vesicles containing the NMDAR subunits NR1 and NR2B, the microtubule-dependent motor protein KIF17, and the postsynaptic adaptor proteins CASK and SAP97. Our data demonstrate that the retention and trafficking of NMDARs in this endoplasmic reticulum subcompartment requires both CASK and SAP97. These findings indicate that NMDARs are sorted away from AMPARs via a non-conventional secretory pathway that utilizes dendritic Golgi outposts.