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The Journal of Neuroscience, January 25, 2006, 26(4):1164-1174; doi:10.1523/JNEUROSCI.3116-05.2006

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Cellular/Molecular
Transition from Reversible to Persistent Binding of CaMKII to Postsynaptic Sites and NR2B

K. Ulrich Bayer,¹ Éric LeBel,^2,3 Greg L. McDonald,^2,4 Heather O’Leary,¹ Howard Schulman,⁵ and Paul De Koninck^2,3

¹Department of Pharmacology and Program in Neuroscience, University of Colorado Health Sciences Center, Denver, Colorado 80262, ²Centre de Recherche Université Laval Robert-Giffard, Québec, Canada G1J 2G3, ³Departments of Biochemistry and Microbiology and ⁴Physics, Laval University, Québec, Canada G1K 7P4, and ⁵Department of Neurobiology, Stanford University, Stanford, California 94305-5125

Correspondence should be addressed to K. Ulrich Bayer, Department of Pharmacology, University of Colorado Health Sciences Center, P.O. Box 6511, Mail Stop 8303, Aurora, CO 80045. Email: ulli.bayer{at}uchsc.edu

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.

Key words: kinase; synapse; plasticity; glutamate; calcium; NMDA receptor

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Received July 27, 2005; revised Oct. 17, 2005; accepted Nov. 29, 2005.

Correspondence should be addressed to K. Ulrich Bayer, Department of Pharmacology, University of Colorado Health Sciences Center, P.O. Box 6511, Mail Stop 8303, Aurora, CO 80045. Email: ulli.bayer{at}uchsc.edu

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