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Target Concepts:
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Query: EC:2.7.11.17 (
CaMKII
)
4,029
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Both long-term potentiation (LTP) and depression (LTD) of excitatory synapse strength require the Ca
2+
/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 Ca
2+
/CaM-stimulated
CaMKII
activity. This unusual regulation was mediated by Ca
2+
/CaM binding to the substrate sites resulting in protection from phosphorylation in the presence of Ca
2+
/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.
...
PMID:CaMKII regulates the depalmitoylation and synaptic removal of the scaffold protein AKAP79/150 to mediate structural long-term depression. 2919 4
Long-term depression (LTD) is a reduction in the efficacy of neuronal synapses, but the molecular basis of LTD signaling and how these signals lead to phenotypic outcomes, such as the shrinkage of synaptic regions, is not clear. In a new report, Woolfrey
et al
use chemically-induced LTD and a multitude of
in vitro
biochemical assays to provide evidence that synaptic removal of the scaffolding protein
AKAP79
/150 promotes LTD-induced spine shrinkage. The further identification of
CaMKII
, a kinase primarily associated with long-term potentiation (LTP), as a requirement for
AKAP79
/150 removal, uncovers unexpected interplay between different post-translational modifications and points to a new model of LTD.
...
PMID:Lipids and phosphates at odds in synaptic depression. 2941 68
