Figure 1.

The D₁ receptor signaling cascades in striatonigral/direct pathway neurons. D₁ receptors couple to at least three distinct signaling cascades: (1) G_s/olf/adenylyl cyclase (AC)/cAMP/PKA/DARPP-32/protein phosphatase-1 (PP-1) signaling (blue; Svenningsson et al., 2004; Stipanovich et al., 2008), (2) G_q/phospholipase C (PLC)/inositol 1,4,5-trisphosphate (IP₃)/IP₃ receptor/Ca²⁺ signaling (orange; Rashid et al., 2007a; Kuroiwa et al., 2008; Hasbi et al., 2009), (3) G_βγ/Src family kinase (SFK)/NMDA receptor NR2B subunit/Ca²⁺/Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1)/ mitogen-activated protein kinase/ERK kinase (MEK)/ERK signaling (green; Girault et al., 2007; Pascoli et al., 2011). The phosphorylation levels of DARPP-32 are low at Thr34 and high at Thr75, Ser97, and Ser130 under basal conditions. Activation of PKA induces the phosphorylation of DARPP-32 at Thr34 and the dephosphorylation of DARPP-32 at Thr75 and Ser97 by PP-2A/B56δ complex, and phospho-Thr34/dephospho-Ser97 DARPP-32 accumulates in nucleus and inhibits PP-1, leading to the increase in histone H3 phosphorylation (Stipanovich et al., 2008). ERK, activated by two D₁ receptor pathways, induces mitogen- and stress-activated kinase 1 (MSK1) activation and histone H3 and cAMP-response element binding protein (CREB) phosphorylation in the nucleus (Girault et al., 2007; Pascoli et al., 2011). Thus, D₁ receptor-mediated activation of PKA, intracellular Ca²⁺, and ERK signaling induces the changes in downstream signaling cascades and the transcriptional activation of many genes. CaMK, Ca²⁺/calmodulin-dependent protein kinase; DAG, diacylglycerol; PDE, phosphodiesterase; STEP, striatal-enriched tyrosine phosphatase.