title: GRIP1 interlinks N-cadherin and AMPA receptors at vesicles to promote combined cargo transport into dendrites.
abstract: 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.
authors.affiliation: Department of Molecular Neurogenetics and Morphology Unit, University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, 20251 Hamburg, Germany.
authors.forename: Frank F
authors.initials: FF
authors.lastname: Heisler
authors.forename: Han Kyu
authors.initials: HK
authors.lastname: Lee
authors.forename: Kira V
authors.initials: KV
authors.lastname: Gromova
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Pechmann
authors.forename: Beate
authors.initials: B
authors.lastname: Schurek
authors.forename: Laura
authors.initials: L
authors.lastname: Ruschkies
authors.forename: Markus
authors.initials: M
authors.lastname: Schroeder
authors.forename: Michaela
authors.initials: M
authors.lastname: Schweizer
authors.forename: Matthias
authors.initials: M
authors.lastname: Kneussel
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism* / Q000648:ultrastructure; D057809:HEK293 Cells; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D022161:Transport Vesicles / Q000378:metabolism*
chemical_list: D015820:Cadherins; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D016547:Kinesins