title: CaMKII translocation requires local NMDA receptor-mediated Ca2+ signaling.
abstract: Excitatory synaptic transmission and plasticity are critically modulated by N-methyl-D-aspartate receptors (NMDARs). Activation of NMDARs elevates intracellular Ca(2+) affecting several downstream signaling pathways that involve Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Importantly, NMDAR activation triggers CaMKII translocation to synaptic sites. NMDAR activation failed to induce Ca(2+) responses in hippocampal neurons lacking the mandatory NMDAR subunit NR1, and no EGFP-CaMKIIalpha translocation was observed. In cells solely expressing Ca(2+)-impermeable NMDARs containing NR1(N598R)-mutant subunits, prolonged NMDA application elevated internal Ca(2+) to the same degree as in wild-type controls, yet failed to translocate CaMKIIalpha. Brief local NMDA application evoked smaller Ca(2+) transients in dendritic spines of mutant compared to wild-type cells. CaMKIIalpha mutants that increase binding to synaptic sites, namely CaMKII-T286D and CaMKII-TT305/306VA, rescued the translocation in NR1(N598R) cells in a glutamate receptor-subtype-specific manner. We conclude that CaMKII translocation requires Ca(2+) entry directly through NMDARs, rather than other Ca(2+) sources activated by NMDARs. Together with the requirement for activated, possibly ligand-bound, NMDARs as CaMKII binding partners, this suggests that synaptic CaMKII accumulation is an input-specific signaling event.
authors.affiliation: Department of Pharmacology, Laboratory for Molecular Pharmacology, University College London, Gower Street, London, UK.
authors.forename: Agnes
authors.initials: A
authors.lastname: Thalhammer
authors.forename: York
authors.initials: Y
authors.lastname: Rudhard
authors.forename: Cezar M
authors.initials: CM
authors.lastname: Tigaret
authors.forename: Kirill E
authors.initials: KE
authors.lastname: Volynski
authors.forename: Dmitri A
authors.initials: DA
authors.lastname: Rusakov
authors.forename: Ralf
authors.initials: R
authors.lastname: Schoepfer
mesh_terms: D000818:Animals; D001120:Arginine / Q000235:genetics; D020013:Calcium Signaling / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D049229:Dendritic Spines / Q000187:drug effects; D051379:Mice; D008959:Models, Neurological; D050505:Mutant Proteins / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects
chemical_list: D050505:Mutant Proteins; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D001120:Arginine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases