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Mechanisms for the Modulation of Dopamine d(1) Receptor Signaling in Striatal Neurons


Mechanisms for the Modulation of Dopamine d(1) Receptor Signaling in Striatal Neurons

Akinori Nishi et al. Front Neuroanat.


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.

Keywords: D1 receptor; DARPP-32; dopamine; phosphodiesterase; signaling; striatum.


Figure 1
Figure 1
The D1 receptor signaling cascades in striatonigral/direct pathway neurons. D1 receptors couple to at least three distinct signaling cascades: (1) Gs/olf/adenylyl cyclase (AC)/cAMP/PKA/DARPP-32/protein phosphatase-1 (PP-1) signaling (blue; Svenningsson et al., ; Stipanovich et al., 2008), (2) Gq/phospholipase C (PLC)/inositol 1,4,5-trisphosphate (IP3)/IP3 receptor/Ca2+ signaling (orange; Rashid et al., ; Kuroiwa et al., ; Hasbi et al., 2009), (3) Gβγ/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., ; 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., ; 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.
Figure 2
Figure 2
D1 receptors form hetero-oligomers with other receptors. Formation of hetero-oligomers with dopamine D1 receptors and other receptors such as D2, D3, A1, and NMDA receptors is shown. Biding of these receptors induces the changes in D1 receptor function and/or localization.
Figure 3
Figure 3
Roles of phosphodiesterases (PDEs) in the control of basal ganglia–thalamocortical circuitry. Output neurons in the striatum are medium spiny neurons (MSNs), which consist of striatonigral/direct pathway and striatopallidal/indirect pathway neurons. Direct pathway neurons are GABAergic, and inhibit tonically active neurons in globus pallidus interna (GPi)/substantia nigra pars reticulata (SNpr). Indirect pathway neurons are also GABAergic, and activate neurons in GPi/SNpr via inhibition of globus pallidus externa (GPe) GABAergic neurons and activation of subthalamic nucleus (STN) glutamatergic neurons. Direct and indirect pathway neurons induce opposing effects on the output neurons in GPi/SNpr, resulting in dis-inhibition and pro-inhibition of output, respectively, to motor areas of the thalamus and cortex. The inhibition of PDEs increases cAMP/PKA signaling in both direct and indirect pathway neurons. PDE inhibitors that predominantly act in direct pathway neurons work like dopamine D1 receptor agonists and activate motor function, whereas PDE inhibitors that predominantly act in indirect pathway neurons work like dopamine D2 receptor antagonists and inhibit motor function. SNpc, substantia nigra pars compacta. Reproduced with permission from reference Nishi and Snyder (2010).

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