title: Differential control of postsynaptic density scaffolds via actin-dependent and -independent mechanisms.
abstract: Organization and dynamic remodeling of postsynaptic density (PSD) are thought to be critical in postsynaptic signal transduction, but the underlying molecular mechanisms are not well understood. We show here that four major scaffolding molecules, PSD-95, GKAP, Shank, and PSD-Zip45, show distinct instability in total molecular content per synapse. Fluorescence recovery after photobleaching also confirmed their distinct turnover rates. Among the PSD molecules examined, PSD-95 was most stable, but its elimination did not influence the dynamics of its direct binding partner GKAP. Multiple interactions of scaffolding molecules with the actin cytoskeleton have suggested their importance in both maintenance and remodeling of the PSD. Indeed, acute pharmacological disruption of F-actin rapidly eliminated the dynamic fraction of GKAP, Shank, and PSD-Zip45, without changing synaptic localization of PSD-95. GKAP content in synapses increased after pharmacological enhancement of neuronal activity, whereas Shank and PSD-Zip45 content showed reduction. Inhibition of F-actin dynamics prevented activity-dependent redistribution of all three scaffolds. We also assessed involvement of glutamate receptors in the regulation of PSD dynamics. Genetic manipulations eliminating either NMDA receptors or metabotropic glutamate receptors did not primarily influence mobility of their binding scaffolds. These results collectively indicate a critical role of filamentous actin in determining the extent of dynamic reorganization in PSD molecular composition.
authors.affiliation: Department of Cell Biology, School of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kuriu
authors.forename: Akihiro
authors.initials: A
authors.lastname: Inoue
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Bito
authors.forename: Kenji
authors.initials: K
authors.lastname: Sobue
authors.forename: Shigeo
authors.initials: S
authors.lastname: Okabe
mesh_terms: D000199:Actins / Q000502:physiology*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D000076122:Disks Large Homolog 4 Protein; D036681:Fluorescence Recovery After Photobleaching; D051528:Guanylate Kinases; D000072233:Homer Scaffolding Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000172:deficiency; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency; D000074407:SAP90-PSD95 Associated Proteins; D013570:Synaptic Membranes / Q000378:metabolism / Q000502:physiology*; D014018:Tissue Distribution; D014162:Transfection
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C000614190:Dlgap1 protein, mouse; D000072233:Homer Scaffolding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C409466:NR1 NMDA receptor; D009419:Nerve Tissue Proteins; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D000074407:SAP90-PSD95 Associated Proteins; C512412:SHANK1 protein, mouse; C488222:Shank2 protein, mouse; D051528:Guanylate Kinases