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Cell Rep. 2014 Feb 13;6(3):431-7. doi: 10.1016/j.celrep.2014.01.005. Epub 2014 Jan 30.

Autonomous CaMKII mediates both LTP and LTD using a mechanism for differential substrate site selection.

Author information

1
Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA.
2
Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA.
3
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
4
Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: mark.dellacqua@ucdenver.edu.
5
Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: ulli.bayer@ucdenver.edu.

Abstract

Traditionally, hippocampal long-term potentiation (LTP) of synaptic strength requires Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII) and other kinases, whereas long-term depression (LTD) requires phosphatases. Here, we found that LTD also requires CaMKII and its phospho-T286-induced "autonomous" (Ca(2+)-independent) activity. However, whereas LTP is known to induce phosphorylation of the AMPA-type glutamate receptor (AMPAR) subunit GluA1 at S831, LTD instead induced CaMKII-mediated phosphorylation at S567, a site known to reduce synaptic GluA1 localization. GluA1 S831 phosphorylation by "autonomous" CaMKII was further stimulated by Ca(2+)/CaM, as expected for traditional substrates. By contrast, GluA1 S567 represents a distinct substrate class that is unaffected by such stimulation. This differential regulation caused GluA1 S831 to be favored by LTP-type stimuli (strong but brief), whereas GluA1 S567 was favored by LTD-type stimuli (weak but prolonged). Thus, requirement of autonomous CaMKII in opposing forms of plasticity involves distinct substrate classes that are differentially regulated to enable stimulus-dependent substrate-site preference.

PMID:
24485660
PMCID:
PMC3930569
DOI:
10.1016/j.celrep.2014.01.005
[Indexed for MEDLINE]
Free PMC Article
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