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 D2 receptors, induced a rapid translocation of alpha-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 alpha-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 alpha-CaMKII in response to D4 receptor activation, a D4-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 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.
Gu
Zhenglin
Z
Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, USA.
Jiang
Qian
Q
Yuen
Eunice Y
EY
Yan
Zhen
Z
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000032:analysis / Q000378:metabolism*; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D009474:Neurons / Q000737:chemistry / Q000201:enzymology*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000166:cytology / Q000201:enzymology; D021381:Protein Transport; D051381:Rats; D018091:Receptors, AMPA / Q000819:agonists / Q000378:metabolism; D050638:Receptors, Dopamine D4 / Q000819:agonists*; D013569:Synapses / Q000737:chemistry / Q000201:enzymology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D001549:Benzamides; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018690:Excitatory Amino Acid Agonists; D010879:Piperazines; D018091:Receptors, AMPA; D050638:Receptors, Dopamine D4; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C477501:N-((4-(2-cyanophenyl)-1-piperazinyl)methyl)-3-methylbenzamide