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.

Keywords: biased signaling; desensitization; dimerization; dopamine D2 and D3 receptor; intracellular trafficking; posttranslational modification; signal transduction.

Figure 1

Major posttranslational modification sites of dopamine D₂ receptor and their functional roles. S/T residues highlighted in red indicate GRK-mediated phosphorylation sites; circles filled with yellow and S/T residues highlighted in purple indicate the amino acids responsible for GRK-mediated D₂R endocytosis; S/T residues highlighted in blue indicate PKC-mediated phosphorylation sites.

Figure 2

Major posttranslational modification sites of dopamine D₃ receptor and their functional roles. Circles filled with yellow indicate the amino acids responsible for agonist-induced desensitization; the two S residues highlighted in red indicate PKC-mediated regulatory processes.

Figure 3

Sequence alignment of dopamine D₂ and D₃ receptors. D_2LR represents alternatively spliced long form of dopamine D₂ receptor. The asparagine residues (N) indicated by orange letters located within the N-terminal tail or within the extracellular loops represent potential N-linked glycosylation sites. Asterisks indicate amino acid residues involved in biased signaling. For details, please refer to the text.