Activation of dopamine D4 receptors induces synaptic translocation of Ca2+/calmodulin-dependent protein kinase II in cultured prefrontal cortical neurons

One of the important targets of dopamine D-4 receptors in prefrontal cortex (PFC) is the multifunctional Ca2+/calmodulindependent protein kinase II (CaMKII). In the present study, we investigated the effect of D-4 receptor activation on subcellular localization of CaMKII. We found that activation of D-4 receptors, but not D-2 receptors, induced a rapid translocation of alpha-CaMKII from cytosol to postsynaptic sites in cultured PFC neurons. Activated CaMKII (Thr(286) phospho-CaMKII) was also redistributed to postsynaptic sites after D-4 receptor stimulation. The translocation was blocked by inhibiting the phospholipase C/inositol 1,4,5-trisphosphate receptor/Ca2+ signaling. Point mutation of the calmodulin binding site (Ala(302)), but not the autophosphorylation site (Thr(286)), of alpha-CaMKII prevented the D-4-induced CaMKII translocation. Moreover, D-4 receptors failed to induce CaMKII translocation in the presence of an actin stabilizer, and D-4 activation reduced the binding of CaMKII to F-actin. Concomitant with the synaptic accumulation of alpha-CaMKII in response to D-4 receptor activation, a D-4-induced increase in the CaMKII phosphorylation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor glutamate receptor 1 (GluR1) subunits and the amplitude of AMPA receptor-mediated excitatory postsynaptic currents was also observed. Thus, our results show that D-4 receptor activation induces the synaptic translocation of CaMKII through a mechanism involving Ca2+/calmodulin and F-actin, which facilitates the regulation of synaptic targets of CaMKII, such as AMPA receptors.