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The Journal of Neuroscience, July 27, 2005, 25(30):6971-6983; doi:10.1523/JNEUROSCI.4698-04.2005

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Cellular/Molecular
A Mechanism for Ca²⁺/Calmodulin-Dependent Protein Kinase II Clustering at Synaptic and Nonsynaptic Sites Based on Self-Association

Andy Hudmon,¹ Eric LeBel,^2,4 Hugo Roy,^2,4 Attila Sik,^3,4 Howard Schulman,¹ M. Neal Waxham,^5 * and Paul De Koninck^2,4 *

¹Department of Neurobiology, Stanford University, Stanford, California 94305, ²Département de Biochimie et de Microbiologie, Faculté des Sciences et de Génie, and ³Département de Psychiatrie, FacultédeMédecine, Université Laval, Québec, Canada G1K 7P4, ⁴Centre de Recherche Université Laval Robert-Giffard, Québec, Canada G1J 2G3, and ⁵Department of Neurobiology and Anatomy, University of Texas Health Science Center, Houston, Texas 77030

The activity of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) plays an integral role in regulating synaptic development and plasticity. We designed a live-cell-imaging approach to monitor an activity-dependent clustering of green fluorescent protein (GFP)-CaMKII holoenzymes, termed self-association, a process that we hypothesize contributes to the translocation of CaMKII to synaptic and nonsynaptic sites in activated neurons. We show that GFP-CaMKII self-association in human embryonic kidney 293 (HEK293) cells requires a catalytic domain and multimeric structure, requires Ca²⁺ stimulation and a functional Ca²⁺/CaM-binding domain, is regulated by cellular pH and Thr286 autophosphorylation, and has variable rates of dissociation depending on Ca²⁺ levels. Furthermore, we show that the same rules that govern CaMKII self-association in HEK293 cells apply for extrasynaptic and postsynaptic translocation of GFP-CaMKII in hippocampal neurons. Our data support a novel mechanism for targeting CaMKII to postsynaptic sites after neuronal activation. As such, CaMKII may form a scaffold that, in combination with other synaptic proteins, recruits and localizes additional proteins to the postsynaptic density. We discuss the potential function of CaMKII self-association as a tag of synaptic activity.

Key words: protein translocation; autophosphorylation; postsynaptic density; aggregation; calmodulin; synaptic tag

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Received July 21, 2004; revised June 13, 2005; accepted June 14, 2005.

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