CaMKII, an Enzyme on the Move: Regulation of Temporospatial Localization

The role of autophosphorylation in dynamic activity-dependent translocation of CaMKII to the PSD. Synaptic activity leads to NMDA receptor activation and Ca²⁺ influx allowing Ca²⁺-CaM to bind to CaMKII promoting translocation to the PSD. Autophosphorylation at T²⁸⁶ (bright star) traps CaMKII in the PSD until Ca²⁺ levels decrease and CaM dissociates from CaMKII. CaMKII autophosphorylated at T^{305, 306} (dark star) is unable to rebind CaM, leading to dissociation of CaMKII from the PSD. PP1 activity, which can be overcome by increased PKA activity, dephosphorylates pT²⁸⁶ and facilitates the dissociation process. The cytosolic pool of CaMKII exists as a mixed population of kinases, with respect to their different states of autophosphorylation. Those with residual pT²⁸⁶ are primed to translocate to the PSD rapidly with a lower amplitude synaptic stimulus, whereas kinase with pT305/306 requires cytosolic phosphatase activity to return to the basal state (19, 44, 71).