title: Neurexin-1β binding to neuroligin-1 triggers the preferential recruitment of PSD-95 versus gephyrin through tyrosine phosphorylation of neuroligin-1.
abstract: Adhesion between neurexin-1β (Nrx1β) and neuroligin-1 (Nlg1) induces early recruitment of the postsynaptic density protein 95 (PSD-95) scaffold; however, the associated signaling mechanisms are unknown. To dissociate the effects of ligand binding and receptor multimerization, we compared conditions in which Nlg1 in neurons was bound to Nrx1β or nonactivating HA antibodies. Time-lapse imaging, fluorescence recovery after photobleaching, and single-particle tracking demonstrated that in addition to aggregating Nlg1, Nrx1β binding stimulates the interaction between Nlg1 and PSD-95. Phosphotyrosine immunoblots and pull-down of gephyrin by Nlg1 peptides in vitro showed that Nlg1 can be phosphorylated at a unique tyrosine (Y782), preventing gephyrin binding. Expression of Nlg1 point mutants in neurons indicated that Y782 phosphorylation controls the preferential binding of Nlg1 to PSD-95 versus gephyrin, and accordingly the formation of inhibitory and excitatory synapses. We propose that ligand-induced changes in the Nlg1 phosphotyrosine level control the balance between excitatory and inhibitory scaffold assembly during synapse formation and stabilization.
authors.affiliation: University Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33000 Bordeaux, France.
authors.forename: Grégory
authors.initials: G
authors.lastname: Giannone
authors.forename: Magali
authors.initials: M
authors.lastname: Mondin
authors.forename: Dolors
authors.initials: D
authors.lastname: Grillo-Bosch
authors.forename: Béatrice
authors.initials: B
authors.lastname: Tessier
authors.forename: Edouard
authors.initials: E
authors.lastname: Saint-Michel
authors.forename: Katalin
authors.initials: K
authors.lastname: Czöndör
authors.forename: Matthieu
authors.initials: M
authors.lastname: Sainlos
authors.forename: Daniel
authors.initials: D
authors.lastname: Choquet
authors.forename: Olivier
authors.initials: O
authors.lastname: Thoumine
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017354:Point Mutation; D051381:Rats; D017386:Sequence Homology, Amino Acid; D014443:Tyrosine / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C073441:gephyrin; C093438:neuroligin 1; C086959:neurexin Ibeta; D014443:Tyrosine