title: Regulation of NMDA receptor transport: a KIF17-cargo binding/releasing underlies synaptic plasticity and memory in vivo.
abstract: Regulation of NMDA receptor trafficking is crucial to modulate neuronal communication. Ca(2+)/calmodulin-dependent protein kinase phosphorylates the tail domain of KIF17, a member of the kinesin superfamily, to control NMDA receptor subunit 2B (GluN2B) transport by changing the KIF17-cargo interaction in vitro. However, the mechanisms of regulation of GluN2B transport in vivo and its physiological significance are unknown. We generated transgenic mice carrying wild-type KIF17 (TgS), or KIF17 with S1029A (TgA) or S1029D (TgD) phosphomimic mutations in kif17(-/-) background. TgA/kif17(-/-) and TgD/kif17(-/-) mice exhibited reductions in synaptic NMDA receptors because of their inability to load/unload GluN2B onto/from KIF17, leading to impaired neuronal plasticity, CREB activation, and spatial memory. Expression of GFP-KIF17 in TgS/kif17(-/-) mouse neurons rescued the synaptic and behavioral defects of kif17(-/-) mice. These results suggest that phosphorylation-based regulation of NMDA receptor transport is critical for learning and memory in vivo.
authors.affiliation: Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Xiling
authors.initials: X
authors.lastname: Yin
authors.forename: Xue
authors.initials: X
authors.lastname: Feng
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Takei
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hirokawa
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D019921:Biotinylation / Q000379:methods; D050882:CREB-Binding Protein / Q000378:metabolism; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins; D000076122:Disks Large Homolog 4 Protein; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D016547:Kinesins / Q000172:deficiency / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016297:Mutagenesis, Site-Directed / Q000379:methods; D009154:Mutation / Q000235:genetics; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000235:genetics; D016601:RNA-Binding Proteins; D011930:Reaction Time / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000235:genetics / Q000502:physiology*; D016708:Synaptophysin / Q000378:metabolism; D013997:Time Factors
chemical_list: D004268:DNA-Binding Proteins; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C409642:KIF17 protein, mouse; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; C121001:NR2B NMDA receptor; D009687:Nuclear Proteins; D011500:Protein Synthesis Inhibitors; D016601:RNA-Binding Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C121253:Spen protein, mouse; D016708:Synaptophysin; D049452:Green Fluorescent Proteins; D012694:Serine; D003513:Cycloheximide; D050882:CREB-Binding Protein; D051528:Guanylate Kinases; D016547:Kinesins