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

The dopamine D-4 receptor in prefrontal cortex (PFC) plays a key role in normal mental functions and neuropsychiatric disorders. However, the cellular mechanisms and physiological actions of D-4 receptors remain elusive. In this study, we found that activation of D-4 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 D-4 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 D-4 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 D-4 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 D-4 receptors to regulate CaMKII activity, which could lead to dynamic regulation of many targets of CaMKII by D-4 receptors.