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Bidirectional Regulation of Ca²⁺/Calmodulin-Dependent Protein Kinase II Activity by Dopamine D₄ Receptors in Prefrontal Cortex

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

The dopamine D₄ receptor in prefrontal cortex (PFC) plays a key role in normal mental functions and neuropsychiatric disorders. However, the cellular mechanisms and physiological actions of D₄ receptors remain elusive. In this study, we found that activation of D₄ receptors in PFC exerts a complex regulation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), a multifunctional enzyme critically involved in synaptic plasticity that is fundamental for cognitive and emotional processes. In PFC slices with high neuronal activity, application of the D₄ receptor agonist [4-phenylpiperazinyl)-methyl]benzamide (PD168077) produced a potent reduction of the CaMKII activity, whereas in PFC slices with low neuronal activity, PD168077 caused a marked increase of the CaMKII activity. The D₄ up-regulation of CaMKII activity was through the stimulation of phospholipase C pathway and elevation of intracellular Ca²⁺ via ionsitol-1,4,5-triphosphate receptors. These results reveal a bidirectional regulation of CaMKII activity by PFC D₄ receptors in response to changes in neuronal activity, and a nonclassic signaling pathway underlying the D₄ up-regulation of CaMKII activity. This modulation provides a unique and flexible mechanism for D₄ receptors to regulate CaMKII activity, which could lead to dynamic regulation of many targets of CaMKII by D₄ receptors.

Address correspondence to: Dr. 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

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