Differential regulation of the dopamine D2 and D3 receptors by G protein-coupled receptor kinases and beta-arrestins.
The D(2) and D(3) receptors (D(2)R and D(3)R), which are potential targets for antipsychotic drugs, have a similar structural architecture and signaling pathway. Furthermore, in some brain regions they are expressed in the same cells, suggesting that differences between the two receptors might lie in other properties such as their regulation. In this study we investigated, using COS-7 and HEK-293 cells, the mechanism underlying the intracellular trafficking of the D(2)R and D(3)R. Activation of D(2)R caused G protein-coupled receptor kinase-dependent receptor phosphorylation, a robust translocation of beta-arrestin to the cell membrane, and profound receptor internalization. The internalization of the D(2)R was dynamin-dependent, suggesting that a clathrin-coated endocytic pathway is involved. In addition, the D(2)R, upon agonist-mediated internalization, localized to intracellular compartments distinct from those utilized by the beta(2)-adrenergic receptor. However, in the case of the D(3)R, only subtle agonist-mediated receptor phosphorylation, beta-arrestin translocation to the plasma membrane, and receptor internalization were observed. Interchange of the second and third intracellular loops of the D(2)R and D(3)R reversed their phenotypes, implicating these regions in the regulatory properties of the two receptors. Our studies thus indicate that functional distinctions between the D(2)R and D(3)R may be found in their desensitization and cellular trafficking properties. The differences in their regulatory properties suggest that they have distinct physiological roles in the brain.
Kim
K M
KM
Pharmacology Laboratory, College of Pharmacy, Chonnam National University, Kwang-Ju, 500-757 Korea.
Valenzano
K J
KJ
Robinson
S R
SR
Yao
W D
WD
Barak
L S
LS
Caron
M G
MG
D000818:Animals; D019390:Arrestins / Q000502:physiology*; D019556:COS Cells; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases; D018491:Dopamine Agonists / Q000494:pharmacology; D004705:Endocytosis; D006801:Humans; D008024:Ligands; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D051552:beta-Adrenergic Receptor Kinases; D000071557:beta-Arrestins
D019390:Arrestins; C493593:DRD3 protein, human; D018491:Dopamine Agonists; D008024:Ligands; D018343:Receptors, Adrenergic, beta-2; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D000071557:beta-Arrestins; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases