Abstract
Ca
2+
/calmodulin-dependent protein kinase II (CaMKII) is activated by Ca
2+
entry into neurons. Autophosphorylation of T286 is of special importance because it makes the enzyme active in the absence of Ca
2+
, providing a biochemical memory that is critical for plasticity. To understand the factors controlling the duration of this state of CaMKII, we studied dephosphorylation of CaMKII in the post-synaptic density (PSD), a structure that defines a neuronal subcompartment critical for plasticity. We found that PSD-resident PP1 can dephosphorylate many sites on CaMKII, but not the T286 site that produces Ca
2+
-independent activity. This, together with previous work showing that soluble PP2A cannot dephosphorylate PSD CaMKII, provides a novel explanation for the
in vivo
persistence of T286 phosphorylation: after activated CaMKII translocates from the cytoplasm to the PSD, structural constraints prevent phosphatases from dephosphorylating T286. These results also suggest that the PSD is more than a simple scaffold for synaptic proteins; it may act to regulate the activity of proteins by positioning them in orientations that either prevent or favor specific biochemical reactions.