CaMKII regulates the depalmitoylation and synaptic removal of the scaffold protein AKAP79/150 to mediate structural long-term depression

J Biol Chem. 2018 Feb 2;293(5):1551-1567. doi: 10.1074/jbc.M117.813808. Epub 2017 Dec 1.


Both long-term potentiation (LTP) and depression (LTD) of excitatory synapse strength require the Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) and its autonomous activity generated by Thr-286 autophosphorylation. Additionally, LTP and LTD are correlated with dendritic spine enlargement and shrinkage that are accompanied by the synaptic accumulation or removal, respectively, of the AMPA-receptor regulatory scaffold protein A-kinase anchoring protein (AKAP) 79/150. We show here that the spine shrinkage associated with LTD indeed requires synaptic AKAP79/150 removal, which in turn requires CaMKII activity. In contrast to normal CaMKII substrates, the substrate sites within the AKAP79/150 N-terminal polybasic membrane-cytoskeletal targeting domain were phosphorylated more efficiently by autonomous compared with Ca2+/CaM-stimulated CaMKII activity. This unusual regulation was mediated by Ca2+/CaM binding to the substrate sites resulting in protection from phosphorylation in the presence of Ca2+/CaM, a mechanism that favors phosphorylation by prolonged, weak LTD stimuli versus brief, strong LTP stimuli. Phosphorylation by CaMKII inhibited AKAP79/150 association with F-actin; it also facilitated AKAP79/150 removal from spines but was not required for it. By contrast, LTD-induced spine removal of AKAP79/150 required its depalmitoylation on two Cys residues within the N-terminal targeting domain. Notably, such LTD-induced depalmitoylation was also blocked by CaMKII inhibition. These results provide a mechanism how CaMKII can indeed mediate not only LTP but also LTD through regulated substrate selection; however, in the case of AKAP79/150, indirect CaMKII effects on palmitoylation are more important than the effects of direct phosphorylation. Additionally, our results provide the first direct evidence for a function of the well-described AKAP79/150 trafficking in regulating LTD-induced spine shrinkage.

Keywords: AKAP79/150; Ca2+/calmodulin-dependent protein kinase II (CaMKII); calmodulin (CaM); dendritic spine; long-term depression (LTD); synapse; synaptic plasticity.

Publication types

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

MeSH terms

  • A Kinase Anchor Proteins / metabolism*
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Humans
  • Lipoylation*
  • Long-Term Potentiation*
  • Long-Term Synaptic Depression*
  • Protein Processing, Post-Translational*
  • Spine / metabolism*
  • Spine / pathology
  • Synapses / metabolism*
  • Synapses / pathology


  • A Kinase Anchor Proteins
  • AKAP5 protein, human
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2