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 D₄ receptors in prefrontal cortex (PFC) is the multifunctional Ca²⁺/calmodulin- dependent protein kinase II (CaMKII). In the present study, we investigated the effect of D₄ receptor activation on subcellular localization of CaMKII. We found that activation of D₄ receptors, but not D ₂ receptors, induced a rapid translocation of α-CaMKII from cytosol to postsynaptic sites in cultured PFC neurons. Activated CaMKII (Thr²⁸⁶ phospho-CaMKII) was also redistributed to postsynaptic sites after D₄ receptor stimulation. The translocation was blocked by inhibiting the phospholipase C/inositol 1,4,5-trisphosphate receptor/Ca ²⁺ signaling. Point mutation of the calmodulin binding site (Ala ³⁰²), but not the autophosphorylation site (Thr²⁸⁶), of α-CaMKII prevented the D₄-induced CaMKII translocation. Moreover, D₄ receptors failed to induce CaMKII translocation in the presence of an actin stabilizer, and D₄ activation reduced the binding of CaMKII to F-actin. Concomitant with the synaptic accumulation of α-CaMKII in response to D₄ receptor activation, a D ₄-induced increase in the CaMKII phosphorylation of α-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 D₄ 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.