Differential regulation of the dopamine D-2 and D-3 receptors by G protein-coupled receptor kinases and beta-arrestins

The D-2 and D-3 receptors (D2R and D3R), which are potential targets for an tipsychotic drugs, have a similar structural architecture and signaling pat hway. Furthermore, in some brain regions they are expressed in the same cel ls, suggesting that differences between the two receptors might lie in othe r properties such as their regulation. In this study we investigated, using COS-7 and HEK-293 cells, the mechanism underlying the intracellular traffi cking of the D2R and D3R. Activation of D2R caused G protein-coupled recept or kinase-dependent receptor phosphorylation, a robust translocation of bet a -arrestin to the cell membrane, and profound receptor internalization. Th e internalization of the D2R was dynamin-dependent, suggesting that a clath rin-coated endocytic pathway is involved. In addition, the D2R, upon agonis t-mediated internalization, localized to intracellular compartments distinc t from those utilized by the B-2-adrenergic receptor. However, in the case of the D3R, only subtle agonist-mediated receptor phosphorylation, beta -ar restin translocation to the plasma membrane, and receptor internalization w ere observed. Interchange of the second and third intracellular loops of th e D2R and D3R reversed their phenotypes, implicating these regions in the r egulatory properties of the two receptors. Our studies thus indicate that f unctional distinctions between the D2R and D3R may be found in their desens itization and cellular trafficking properties. The differences in their reg ulatory properties suggest that they have distinct physiological roles in t he brain.