Unveiling the Differences in Signaling and Regulatory Mechanisms between Dopamine D2 and D3 Receptors and Their Impact on Behavioral Sensitization

Abstract

Dopamine receptors are classified into five subtypes, with D2R and D3R playing a crucial role in regulating mood, motivation, reward, and movement. Whereas D2R are distributed widely across the brain, including regions responsible for motor functions, D3R are primarily found in specific areas related to cognitive and emotional functions, such as the nucleus accumbens, limbic system, and prefrontal cortex. Despite their high sequence homology and similar signaling pathways, D2R and D3R have distinct regulatory properties involving desensitization, endocytosis, posttranslational modification, and interactions with other cellular components. In vivo, D3R is closely associated with behavioral sensitization, which leads to increased dopaminergic responses. Behavioral sensitization is believed to result from D3R desensitization, which removes the inhibitory effect of D3R on related behaviors. Whereas D2R maintains continuous signal transduction through agonist-induced receptor phosphorylation, arrestin recruitment, and endocytosis, which recycle and resensitize desensitized receptors, D3R rarely undergoes agonist-induced endocytosis and instead is desensitized after repeated agonist exposure. In addition, D3R undergoes more extensive posttranslational modifications, such as glycosylation and palmitoylation, which are needed for its desensitization. Overall, a series of biochemical settings more closely related to D3R could be linked to D3R-mediated behavioral sensitization.

Arrestin-3-assisted activation of JNK3 mediates dopaminergic behavioral sensitization

“…All five DA receptors are GPCRs and interact with arrestins, although the mode of interaction and its functional consequences are unique for each subtype. 17 , 18 , 19 , 20 , 21 , 22 Long-term use of dopaminergic drugs causes persistent changes in DA-dependent behaviors. In rodents with unilateral ablation of the dopaminergic input to the striatum, stimulation with dopaminergic agonists or the DA precursor L-DOPA causes persistent behavioral and molecular sensitization (reviewed in the study by Bastide et al.…”

G Protein-Coupled Receptor Kinase 2 Selectively Enhances β-Arrestin Recruitment to the D2 Dopamine Receptor through Mechanisms That Are Independent of Receptor Phosphorylation

“…Similarly, the GRK specificity for regulating D2R signaling is not entirely clear. Most studies have implicated the GRK2/3 subfamily in modulating the D2R [17,[21][22][23][24][25], although it is not known if GRK2 and GRK3 are equally effective in this regard. Further, the role of other GRKs, such as GRK6, in regulating the D2R has been postulated [26,27].…”

CHL1 depletion affects dopamine receptor D2-dependent modulation of mouse behavior

“…DA serves its function by activating five subtypes of receptors (D1-D5), which are abundant in the brain. They are classified into two general classes: those that predominantly couple to the Gαs/olf class of G proteins ("D1-like"; D1 and D5 receptors), and to the Gαi/o class of G proteins ("D2-like"; D2-D4 receptors) (Kebabian and Calne, 1979;Lachowicz and Sibley, 1997;Kim, 2023). The D2 receptor (D2R) is expressed pre-and postsynaptically and maintains continuous signal transduction through agonist-induced receptor phosphorylation, arrestin recruitment, and endocytosis, which recycle and resensitize desensitized receptors (Kim, 2023).…”

“…They are classified into two general classes: those that predominantly couple to the Gαs/olf class of G proteins ("D1-like"; D1 and D5 receptors), and to the Gαi/o class of G proteins ("D2-like"; D2-D4 receptors) (Kebabian and Calne, 1979;Lachowicz and Sibley, 1997;Kim, 2023). The D2 receptor (D2R) is expressed pre-and postsynaptically and maintains continuous signal transduction through agonist-induced receptor phosphorylation, arrestin recruitment, and endocytosis, which recycle and resensitize desensitized receptors (Kim, 2023). Activation of the D2Rs and interaction with Gαi/o inhibits the activation of adenylyl cyclase, production of cyclic adenosine monophosphate and activation of protein kinase A (Neve et al, 2004;Beaulieu and Gainetdinov, 2011).…”