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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Hippocampus / enzymology
  • Hippocampus / physiology
  • Long-Term Potentiation / physiology*
  • Long-Term Synaptic Depression / physiology*
  • Mice
  • Molecular Sequence Data
  • Phosphorylation
  • Phosphoserine / metabolism
  • Receptors, AMPA / chemistry
  • Receptors, AMPA / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Substrate Specificity


  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Phosphoserine
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • glutamate receptor ionotropic, AMPA 1