Elsevier Inc. Ptpn5 ventral tegmental area (VTA) <--> prefrontal cortex (PFC) substantia nigra pars compacta (SNc) ---> prefrontal cortex (PFC) ventral tegmental area (VTA) substantia nigra pars compacta (SNc) dopamine dopamine biosynthetic pathway Gnao1 Gnai2 Gnal G protein mediated signaling pathway via Galphas family G protein mediated signaling pathway via Galphai family D1-like receptor Arrb2 ---> G protein independent DA signaling D2-like receptor ventral tegmental area (VTA) <--> nucleus accumbens (NAc) substantia nigra pars compacta (SNc) ---> dorsal striatum/caudate-putamen D1-like receptor ---- dopamine D2-like receptor ---- dopamine DA receptor heteromer ---- dopamine Ca2+ protein kinase C (PKC) signaling pathway calcium/calcium-mediated signaling pathway calcium transport pathway protein kinase A (PKA) signaling pathway Ppp1r1b kinases/phosphatases nucleus accumbens (NAc) prefrontal cortex (PFC) the extracellular signal-regulated Raf/Mek/Erk signaling pathway G protein mediated signaling pathway via Galphaq family thalamus --+> cortical areas DA receptor heteromer cortical areas G protein independent DA signaling motivation prefrontal cortex (PFC) --+> nucleus accumbens (NAc) reward action selection, motor function substantia nigra pars reticulata (SNr) ---| thalamus nucleus accumbens (NAc) ---> ventral pallidum (VP) ventral pallidum (VP) ---> cortical areas GRK in DA signaling Ppp1c Ptpn5 ---| the extracellular signal-regulated Raf/Mek/Erk signaling pathway Ppp1c --+> Ptpn5 globus pallidus, external (GPe) subthalamic nucleus (STN) --+> substantia nigra pars reticulata (SNr) subthalamic nucleus (STN) thalamus Ppp1r1b kinases/phosphatases ---> Ppp1r1b Ppp1r1b ---> protein kinase A (PKA) signaling pathway protein kinase A (PKA) signaling pathway ---> Ppp1r1b GRK in DA signaling ---> D2-like receptor cortical areas --+> dorsal striatum/caudate-putamen dorsal striatum/caudate-putamen globus pallidus, external (GPe) ---| subthalamic nucleus (STN) Ppp1r1b ---| Ppp1c dorsal striatum/caudate-putamen ---| substantia nigra pars reticulata (SNr) dorsal striatum/caudate-putamen ---| globus pallidus, external (GPe) Ppp1r1b kinases/phosphatases ---> Ppp1r1b nucleus accumbens (NAc) ---> substantia nigra pars reticulata (SNr) diacylglycerol --+> protein kinase C (PKC) signaling pathway Arrb2 ---- D1-like receptor Arrb2 ---- D2-like receptor Arrb1 ---- D1-like receptor Arrb1 Arrb1 ---- D2-like receptor GRK in DA signaling ---> D1-like receptor Arrb2 Ppp1r1b cortical areas --+> nucleus accumbens (NAc) RGS in DA signaling ---| Gnal RGS in DA signaling ---| Gnai2 RGS in DA signaling RGS in DA signaling ---| Gnao1 cAMP --+> protein kinase A (PKA) signaling pathway G protein mediated signaling pathway via Galphas family --+> Adcy5 ATP ---> cAMP Adcy5 G protein mediated signaling pathway via Galphai family ---| Adcy5 IP3 --+> Ca2+ G protein mediated signaling pathway via Galphaq family --+> IP3 G protein mediated signaling pathway via Galphaq family --+> diacylglycerol substantia nigra pars reticulata (SNr) associative learning cognitive flexibility working memory ventral pallidum (VP) ATP cAMP IP3 diacylglycerol