Mechanisms for the modulation of dopamine D1 receptor signaling in striatal neurons

In the striatum, dopamine D-1 receptors are preferentially expressed in striatonigral neurons, and increase the neuronal excitability, leading to the increase in GABAergic inhibitory output to substantia nigra pars reticulata. Such roles of D-1 receptors are important for the control of motor functions. In addition, the roles of D-1 receptors are implicated in reward, cognition, and drug addiction. Therefore, elucidation of mechanisms for the regulation of dopamine D-1 receptor signaling is required to identify therapeutic targets for Parkinson's disease and drug addiction. D-1 receptors are coupled to G(s/olf)/adenylyl cyclase/PKA signaling, leading to the phosphorylation of PKA substrates including DARPP-32. Phosphorylated form of DARPP-32 at Thr34 has been shown to inhibit protein phosphatase-1, and thereby controls the phosphorylation states and activity of many downstream physiological effectors. Roles of DARPP-32 and its phosphorylation at Thr34 and other sites in D-1 receptor signaling are extensively studied. In addition, functional roles of the non-canonical D-1 receptor signaling cascades that coupled to G(q)/phospholipase C or Src family kinase become evident. We have recently shown that phosphodiesterases (PDEs), especially PDE10A, play a pivotal role in regulating the tone of D-1 receptor signaling relatively to that of D-2 receptor signaling. We review the current understanding of molecular mechanisms for the modulation of D-1 receptor signaling in the striatum.