title: Transition from reversible to persistent binding of CaMKII to postsynaptic sites and NR2B.
abstract: Changes in protein-protein interactions and activity states have been proposed to underlie persistent synaptic remodeling that is induced by transient stimuli. Here, we show an unusual stimulus-dependent transition from a short-lived to long-lasting binding between a synaptic receptor and its transducer. Both molecules, the NMDA receptor subunit NR2B and Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII), are strongly implicated in mediating synaptic plasticity. We show that CaMKII reversibly translocates to synaptic sites in response to brief stimuli, but its resident time at the synapse increases after longer stimulation. Thus, CaMKII localization reflects temporal patterns of synaptic stimulation. We have identified two surface regions of CaMKII involved in short-lived and long-term interactions with NR2B. Our results support an initial reversible and Ca2+/CaM-dependent binding at the substrate-binding site ("S-site"). On longer stimulation, a persistent interaction is formed at the T286-binding site ("T-site"), thereby keeping the autoregulatory domain displaced and enabling Ca2+/CaM-independent kinase activity. Such dual modes of interaction were observed in vitro and in HEK cells. In hippocampal neurons, short-term stimulation initiates a reversible translocation, but an active history of stimulation beyond some threshold produces a persistent synaptic localization of CaMKII. This activity-dependent incorporation of CaMKII into postsynaptic sites may play a role in maturation and plasticity of synapses.
authors.affiliation: Department of Pharmacology, Program in Neuroscience, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. ulli.bayer@uchsc.edu
authors.forename: K Ulrich
authors.initials: KU
authors.lastname: Bayer
authors.forename: Eric
authors.initials: E
authors.lastname: LeBel
authors.forename: Greg L
authors.initials: GL
authors.lastname: McDonald
authors.forename: Heather
authors.initials: H
authors.lastname: O'Leary
authors.forename: Howard
authors.initials: H
authors.lastname: Schulman
authors.forename: Paul
authors.initials: P
authors.lastname: De Koninck
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D007668:Kidney; D008958:Models, Molecular; D020125:Mutation, Missense; D016202:N-Methylaspartate / Q000494:pharmacology; D009473:Neuronal Plasticity; D010766:Phosphorylation; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D013569:Synapses / Q000737:chemistry* / Q000648:ultrastructure; D014162:Transfection
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D020033:Protein Isoforms; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D015759:Ionomycin; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium; D005998:Glycine