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Activation of Dopamine D₄ Receptors Induces Synaptic Translocation of Ca²⁺/Calmodulin-Dependent Protein Kinase II in Cultured Prefrontal Cortical Neurons

Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York

One of the important targets of dopamine D₄ receptors in prefrontal cortex (PFC) is the multifunctional Ca²⁺/calmodulindependent 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 D₂ receptors, induced a rapid translocation of -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/Ca²⁺ signaling. Point mutation of the calmodulin binding site (Ala³⁰²), but not the autophosphorylation site (Thr²⁸⁶), of -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 -CaMKII in response to D₄ receptor activation, a D₄-induced increase in the CaMKII phosphorylation of -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.

Address correspondence to: Zhen Yan, Department of Physiology and Biophysics, State University of New York at Buffalo, 124 Sherman Hall, Buffalo, NY 14214. E-mail: zhenyan{at}buffalo.edu