Novel insights into CaMKII function and regulation during memory formation.

Ca(2+)/calmodulin-dependent kinase II (CaMKII) is an abundant synaptic signalling molecule that is essential for memory formation and the induction of synaptic potentiation. Additionally, CaMKII plays a prominent role in synaptic tagging and metaplasticity. These abilities are mediated by kinase activity as well as binding to a wide variety of synaptic proteins, including NMDA receptor subunits, modulating CaMKII location and activity. A characteristic feature is that autophosphorylation of CaMKII switches the kinase into autonomous activity. Since CaMKII can be autonomously active and because CaMKII is required for the formation of memory it is important that the kinase activity is adequately switched off. However, the exact time window of increased activity and how this is terminated, it is still matter of debate. After training in a memory task CaMKII activity is increased for at least 30 min. This CaMKII activity and further activation of CaMKII may be regulated by changes in the expression of two endogenous CaMKII inhibitor proteins, CaMKII inhibitor Alpha and Beta, as they are up-regulated early after training. These endogenous inhibitors specifically block CaMKII activity and they inhibit the association with NMDA receptor subunits. Thus, regulation of the expression of endogenous CaMKII inhibitors may constitute a novel negative feedback on CaMKII signalling during memory formation.