Classically the D R family activates the G s

Classically, the D1R family activates the Gαs/olf family of G proteins, leading to activation of adenylyl cyclase (AC) and increased cAMP production, whereas the D2R class recruits Gαi/o signaling to inhibit AC and cAMP production (Beaulieu and Gainetdinov, 2011). In striatal spiny projection neurons (SPNs), these well-studied signaling pathways are known to influence protein kinase A (PKA) activity as well as the phosphorylation state of various proteins. One such protein, DARPP-32, acts as a signal transduction integrator to modulate the activity of key kinases and phosphatases, altering neuronal excitability and gene expression (Svenningsson et al., 2004). Dopamine receptors may modulate the function of various ion channels through Gα-mediated mechanisms but also via Gβγ subunits, effectively regulating intracellular Ca2+ levels and excitability in striatal neurons (Beaulieu and Gainetdinov, 2011). A vast body of work using electrophysiological recordings in acute neuronal or slice preparations has demonstrated that in SPNs, pharmacological activation of D1Rs and D2Rs generally elicits the opposite effects on the function of L-type calcium channels, K+ channels, and on the trafficking and function of glutamatergic α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) and N-methyl-D-aspartic Tacedinaline (NMDA) receptors (Cepeda et al., 1993; Galarraga et al., 1997; Greif et al., 1995; Hallett et al., 2006; Hernandez-Echeagaray et al., 2004; Hernandez-Lopez et al., 1997, 2000; Kitai and Surmeier, 1993; Snyder et al., 2000; Surmeier et al., 1995). D1R activation is thus thought to favor increased excitability and heightened Ca2+ entry into SPNs, while the opposite is generally assumed following D2R activation, but the outcome may differ depending on the state of the cell, as well as on recording conditions (Nicola et al., 2000). D1 and D2Rs also may signal via G-protein independent mechanisms. One such mechanism involves the β-arrestins. While primarily known for their roles in desensitization and internalization of GPCRs, β-arrestins may also engage various signaling cascades (Beaulieu and Gainetdinov, 2011; Shenoy and Lefkowitz, 2011). In response to dopamine binding, for example, dopamine receptors recruit β-arrestins (β-arrestin-1 and -2), which terminates G protein signaling and facilitates receptor endocytosis (Beaulieu and Gainetdinov, 2011; Kim et al., 2001). Based on several in vivo studies, it has been proposed that D2Rs promote, via β-arrestin-2, the inactivation of Akt and the subsequent activation of glycogen synthase kinase 3 (GSK-3), whereas D1Rs preferentially activate β-arrestin-2-mediated ERK signaling (Beaulieu et al., 2004, 2005, 2007; Urs et al., 2011).
Localization of D2 receptors in striatum One characteristic of D2Rs that has complicated their study is their expression in multiple neuronal populations within striatum, both pre- and postsynaptically (Beaulieu and Gainetdinov, 2011). In addition to spiny projection neurons (SPNs), which are the principal cells of the striatum, D2R expression has been demonstrated in cholinergic interneurons (CINs), as well as in axon terminals of DA and cortical neurons, all of which are key players in controlling striatal output and behavior.