DA neurons are capable of somatodendritic and axonal DA rele
DA neurons are capable of somatodendritic and axonal DA release, which may occur at synapses, as well as non-synaptic or asynaptic sites (Trudeau et al., 2014). DA may also be released at different timescales and in response to different DA neuron firing patterns (Grace et al., 2007). Furthermore, subpopulations of DA neurons may exhibit unique electrophysiological and pharmacological properties (Morales and Margolis, 2017). Accumulating evidence also supports the ability of DA to be co-released with other neurotransmitters such as glutamate and GABA, further emphasizing the intricate nature of dopamine neuron-derived signals in the Sodium Orthovanadate structure (Trudeau et al., 2014). The complex neuroanatomical and functional organization leading to DA synthesis and release is matched by DA\'s actions on its different receptors, pre- and postsynaptically.
Dopamine receptor classes DA exerts its neurochemical influence on cells through its actions on two main families of G-protein coupled receptors (GPCRs): the D1 receptor (D1R) and the D2 receptor (D2R) families. The D1R family is composed of D1R and D5R, whereas the D2R family consists of D2R, D3R, and D4R. D1Rs and D2Rs have been the most widely studied, in part because they are the most densely expressed throughout dorsal and ventral striatum, but also due to their contrasting regulation of cellular signaling and activity. However, it is becoming increasingly evident that the other receptor subtypes (D3-D5R) also play key roles in shaping striatal functions (Centonze et al., 2003; Cote et al., 2014; Dulawa et al., 1999; Rubinstein et al., 1997; Simpson et al., 2014; Song et al., 2012). 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 acid (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).