title: NCAM promotes assembly and activity-dependent remodeling of the postsynaptic signaling complex.
abstract: The neural cell adhesion molecule (NCAM) regulates synapse formation and synaptic strength via mechanisms that have remained unknown. We show that NCAM associates with the postsynaptic spectrin-based scaffold, cross-linking NCAM with the N-methyl-d-aspartate (NMDA) receptor and Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIalpha) in a manner not firmly or directly linked to PSD95 and alpha-actinin. Clustering of NCAM promotes formation of detergent-insoluble complexes enriched in postsynaptic proteins and resembling postsynaptic densities. Disruption of the NCAM-spectrin complex decreases the size of postsynaptic densities and reduces synaptic targeting of NCAM-spectrin-associated postsynaptic proteins, including spectrin, NMDA receptors, and CaMKIIalpha. Degeneration of the spectrin scaffold in NCAM-deficient neurons results in an inability to recruit CaMKIIalpha to synapses after NMDA receptor activation, which is a critical process in NMDA receptor-dependent long-term potentiation. The combined observations indicate that NCAM promotes assembly of the spectrin-based postsynaptic signaling complex, which is required for activity-associated, long-lasting changes in synaptic strength. Its abnormal function may contribute to the etiology of neuropsychiatric disorders associated with mutations in or abnormal expression of NCAM.
authors.affiliation: Zentrum für Molekulare Neurobiologie, Universität Hamburg, 20246 Hamburg, Germany.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Sytnyk
authors.forename: Iryna
authors.initials: I
authors.lastname: Leshchyns'ka
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Nikonenko
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
mesh_terms: D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000502:physiology*; D019006:Neural Cell Adhesion Molecules / Q000502:physiology*; D009474:Neurons / Q000166:cytology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013049:Spectrin / Q000502:physiology
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D016194:Receptors, N-Methyl-D-Aspartate; C033652:postsynaptic density proteins; D013049:Spectrin; D017871:Calcium-Calmodulin-Dependent Protein Kinases