GRIP1 interlinks N-cadherin and AMPA receptors at vesicles to promote combined cargo transport into dendrites
The GluA2 subunit of AMPA-type glutamate receptors (AMPARs) regulates excitatory synaptic transmission in neurons. In addition, the transsynaptic cell adhesion molecule N -cadherin controls excitatory synapse function and stabilizes dendritic spine structures. At postsynaptic membranes, GluA2 physic...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 13; pp. 5030 - 5035 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
01.04.2014
National Acad Sciences |
Subjects | |
Online Access | Get full text |
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Summary: | The GluA2 subunit of AMPA-type glutamate receptors (AMPARs) regulates excitatory synaptic transmission in neurons. In addition, the transsynaptic cell adhesion molecule N -cadherin controls excitatory synapse function and stabilizes dendritic spine structures. At postsynaptic membranes, GluA2 physically binds N -cadherin, underlying spine growth and synaptic modulation. We report that N -cadherin binds to PSD-95/SAP90/DLG/ZO-1 (PDZ) domain 2 of the glutamate receptor interacting protein 1 (GRIP1) through its intracellular C terminus. N -cadherin and GluA2-containing AMPARs are presorted to identical transport vesicles for dendrite delivery, and live imaging reveals cotransport of both proteins. The kinesin KIF5 powers GluA2/ N -cadherin codelivery by using GRIP1 as a multilink interface. Notably, GluA2 and N -cadherin use different PDZ domains on GRIP1 to simultaneously bind the transport complex, and interference with either binding motif impairs the turnover of both synaptic cargoes. Depolymerization of microtubules, deletion of the KIF5 motor domain, or specific blockade of AMPAR exocytosis affects delivery of GluA2/ N -cadherin vesicles. At the functional level, interference with this cotransport reduces the number of spine protrusions and excitatory synapses. Our data suggest the concept that the multi-PDZ-domain adaptor protein GRIP1 can act as a scaffold at trafficking vesicles in the combined delivery of AMPARs and N -cadherin into dendrites. |
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Bibliography: | http://dx.doi.org/10.1073/pnas.1304301111 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by Richard L. Huganir, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved February 20, 2014 (received for review March 7, 2013) Author contributions: F.F.H., H.K.L., and M.K. designed research; F.F.H., H.K.L., K.V.G., Y.P., B.S., L.R., M. Schroeder, and M. Schweizer performed research; F.F.H., H.K.L., K.V.G., M. Schweizer, and M.K. analyzed data; and F.F.H. and M.K. wrote the paper. 1F.F.H. and H.K.L. contributed equally to this work. |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.1304301111 |