title: Shisa6 traps AMPA receptors at postsynaptic sites and prevents their desensitization during synaptic activity.
abstract: Trafficking and biophysical properties of AMPA receptors (AMPARs) in the brain depend on interactions with associated proteins. We identify Shisa6, a single transmembrane protein, as a stable and directly interacting bona fide AMPAR auxiliary subunit. Shisa6 is enriched at hippocampal postsynaptic membranes and co-localizes with AMPARs. The Shisa6 C-terminus harbours a PDZ domain ligand that binds to PSD-95, constraining mobility of AMPARs in the plasma membrane and confining them to postsynaptic densities. Shisa6 expressed in HEK293 cells alters GluA1- and GluA2-mediated currents by prolonging decay times and decreasing the extent of AMPAR desensitization, while slowing the rate of recovery from desensitization. Using gene deletion, we show that Shisa6 increases rise and decay times of hippocampal CA1 miniature excitatory postsynaptic currents (mEPSCs). Shisa6-containing AMPARs show prominent sustained currents, indicating protection from full desensitization. Accordingly, Shisa6 prevents synaptically trapped AMPARs from depression at high-frequency synaptic transmission.
authors.affiliation: Department Molecular and Cellular Neurobiology, 1081 HV Amsterdam, The Netherlands.
authors.forename: Remco V
authors.initials: RV
authors.lastname: Klaassen
authors.affiliation: Department Molecular and Cellular Neurobiology, 1081 HV Amsterdam, The Netherlands.|Department Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.
authors.forename: Jasper
authors.initials: J
authors.lastname: Stroeder
authors.affiliation: University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33000 Bordeaux, France.|CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33000 Bordeaux, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Coussen
authors.affiliation: University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33000 Bordeaux, France.|CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33000 Bordeaux, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Hafner
authors.affiliation: University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33000 Bordeaux, France.|CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33000 Bordeaux, France.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Petersen
authors.affiliation: University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33000 Bordeaux, France.|CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33000 Bordeaux, France.
authors.forename: Cedric
authors.initials: C
authors.lastname: Renancio
authors.affiliation: Department Molecular and Cellular Neurobiology, 1081 HV Amsterdam, The Netherlands.
authors.forename: Leanne J M
authors.initials: LJ
authors.lastname: Schmitz
authors.affiliation: University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33000 Bordeaux, France.|CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33000 Bordeaux, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Normand
authors.affiliation: Department Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.
authors.forename: Johannes C
authors.initials: JC
authors.lastname: Lodder
authors.affiliation: Department Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.
authors.forename: Diana C
authors.identifier: http://orcid.org/0000-0002-0724-3596
authors.initials: DC
authors.lastname: Rotaru
authors.affiliation: Department Molecular and Cellular Neurobiology, 1081 HV Amsterdam, The Netherlands.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Rao-Ruiz
authors.affiliation: Department Molecular and Cellular Neurobiology, 1081 HV Amsterdam, The Netherlands.
authors.forename: Sabine
authors.initials: S
authors.lastname: Spijker
authors.affiliation: Department Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.
authors.forename: Huibert D
authors.initials: HD
authors.lastname: Mansvelder
authors.affiliation: University of Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33000 Bordeaux, France.|CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33000 Bordeaux, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Choquet
authors.affiliation: Department Molecular and Cellular Neurobiology, 1081 HV Amsterdam, The Netherlands.
authors.forename: August B
authors.initials: AB
authors.lastname: Smit
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D055724:Electrophysiological Phenomena; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D051381:Rats; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D013569:Synapses; D020798:Two-Hybrid System Techniques
chemical_list: D008565:Membrane Proteins; D018091:Receptors, AMPA; C514669:Shisa protein, mouse