A mechanism for Ca2+/calmodulin-dependent protein kinase II clustering at synaptic and nonsynaptic sites based on self-association

Andy Hudmon, Eric LeBel, Hugo Roy, Attila Sik, Howard Schulman, M. Neal Waxham, Paul De Koninck

Research output: Contribution to journalArticle

118 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6971-6983
Number of pages13
JournalJournal of Neuroscience
Volume25
Issue number30
DOIs
StatePublished - Jul 27 2005

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Keywords

  • Aggregation
  • Autophosphorylation
  • Calmodulin
  • Postsynaptic density
  • Protein translocation
  • Synaptic tag

ASJC Scopus subject areas

  • Neuroscience(all)

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