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 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.