QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.107.043885v1 74/1/59    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Fiorentini, C. Articles by Missale, C. PubMed PubMed Citation Articles by Fiorentini, C. Articles by Missale, C.

Reciprocal Regulation of Dopamine D1 and D3 Receptor Function and Trafficking by Heterodimerization

Section of Pharmacology, Department of Biomedical Sciences and Biotechnology (C.F., C.B., E.G., P.F.S., C.M.), and Centre of Excellence on Diagnostic and Therapeutic Innovation (P.F.S., C.M.), University of Brescia, Brescia, Italy; and Consiglio Nazionale delle Ricerche Institute of Neuroscience, Milano, Italy (C.G.)

Colocalization of dopamine D1 (D1R) and D3 receptors (D3R) in specific neuronal populations suggests that their functional cross-talk might involve direct interactions. Here we report that the D1R coimmunoprecipitates with the D3R from striatal protein preparations, suggesting that they are clustered together in this region. Using bioluminescence resonance energy transfer (BRET²), we further suggest the existence of a physical interaction between D1R and D3R. Tagged D1R and D3R cotransfected in human embryonic kidney (HEK) 293 cells generated a significant BRET² signal that was insensitive to agonist stimulation, suggesting that they form a constitutive heterodimer. D1R and D3R regulate adenylyl cyclase (AC) in opposite ways. In HEK 293 cells coexpressing D1R and D3R, dopamine stimulated AC with higher potency and displaced [³H]R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390) binding with higher affinity than in cells expressing the D1R. In HEK 293 cells individually expressing D1R or D3R, agonist stimulation induces internalization of D1R but not of D3R. Heterodimerization with D3R abolishes agonist-induced D1R cytoplasmic sequestration induced by selective D1R agonists and enables internalization of the D1R/D3R complex in response to the paired stimulation of both D1R and D3R. This mechanism involves β-arrestin binding because it was blocked by mutant β-arrestinV53D. These data suggest that as a result of dimerization, the D3R is switched to the desensitization mechanisms typical of the D1R. These data give a novel insight into how D1R and D3R may function in an integrated way, providing a molecular mechanism by which to converge D1R- and D3R-related dysfunctions.

Address correspondence to: Dr. Cristina Missale, Section of Pharmacology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Viale Europa 11, 25124 Brescia, Italy. E-mail: cmissale{at}med.unibs.it

This article has been cited by other articles:

				D. Marcellino, S. Ferre, V. Casado, A. Cortes, B. Le Foll, C. Mazzola, F. Drago, O. Saur, H. Stark, A. Soriano, et al. Identification of Dopamine D1-D3 Receptor Heteromers: INDICATIONS FOR A ROLE OF SYNERGISTIC D1-D3 RECEPTOR INTERACTIONS IN THE STRIATUM J. Biol. Chem., September 19, 2008; 283(38): 26016 - 26025. [Abstract] [Full Text] [PDF]