Bidirectional regulation of Ca²⁺/calmodulin-dependent protein kinase II activity by dopamine D₄ receptors in prefrontal cortex

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 D ₄ 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 D ₄ receptors.