Autophosphorylation on Thr-286 disables the auto-inhibitory domain, increases the affinity for Ca2+/calmodulin by 1000-fold, and allows the holoenzyme to bind to NMDA receptors.228 The CaMKII holoenzyme is activated to differing degrees depending on the magnitude and duration of the intracellular calcium signal, and autophosphorylation allows for increases in CaMKII activity to persist for hours after levels of intracellular calcium fall.230 Activation of CaMKIIs often involves translocation to target areas and binding to target proteins. Thus, activation of CaMKII can be measured by translocation, or more often by an increase in autophosphorylation or phosphorylation of a specific substrate. CaMKII phosphorylates many substrates important in neuronal function and for responses to addictive drugs including synapsin I at Ser-603,231 CREB at Ser 133 and Ser-142,232 and the AMPA GluR1 subunit at Ser-831.233 Activated CaMKII can also bind to the NR2B subunit of NMDA receptors and contribute to synaptic plasticity and LTP.234 Mutation of the αCaMKII autophosphorylation site Thr-286 abolishes stimulus-evoked LTP in rat hippocampal slices and results in spatial memory deficits in the mutant mice.234 In rat hippocampal cultures, the dopamine D1 agonist
