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J. Biol. Chem., Vol. 283, Issue 38, 26016-26025, September 19, 2008

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Identification of Dopamine D₁–D₃ Receptor Heteromers

INDICATIONS FOR A ROLE OF SYNERGISTIC D₁–D₃ RECEPTOR INTERACTIONS IN THE STRIATUM^*

Daniel Marcellino, Sergi Ferré¹, Vicent Casadó^¶, Antonio Cortés^¶, Bernard Le Foll^||, Carmen Mazzola^**, Filippo Drago^**, Oliver Saur, Holger Stark, Aroa Soriano^¶, Chanel Barnes, Steven R. Goldberg, Carme Lluis^¶, Kjell Fuxe, and Rafael Franco^¶

From the Department of Neuroscience, Karolinska Institute, Stockholm 17177, Sweden, the Behavioral Neuroscience Branch, National Institute on Drug Abuse, Intramural Research Program, Department of Health and Human Services, Baltimore, Maryland 21224, the ^¶Institut d'Investigacio Biomedica August Pi i Sunyer and Department of Biochemistry and Molecular Biology, University of Barcelona, Bacelona 08028, Spain, the ^||Translational Addiction Research Laboratory, Center for Addiction and Mental Health, University of Toronto, Toronto M5S 2S1, Canada, the ^**Department of Experimental and Clinical Pharmacology, University of Catania Medical School, Catania 95125, Italy, and the Institute of Chemical Pharmacology, Johann Wolfgang Goethe University, Frankfurt 60438, Germany

The function of dopamine D₃ receptors present in the striatum has remained elusive. In the present study evidence is provided for the existence of dopamine D₁–D₃ receptor heteromers and for an intramembrane D₁–D₃ receptor cross-talk in living cells and in the striatum. The formation of D₁–D₃ receptor heteromers was demonstrated by fluorescence resonance energy transfer and bioluminescence resonance energy transfer techniques in transfected mammalian cells. In membrane preparations from these cells, a synergistic D₁–D₃ intramembrane receptor-receptor interaction was observed, by which D₃ receptor stimulation enhances D₁ receptor agonist affinity, indicating that the D₁–D₃ intramembrane receptor-receptor interaction is a biochemical characteristic of the D₁–D₃ receptor heteromer. The same biochemical characteristic was also observed in membrane preparations from brain striatum, demonstrating the striatal co-localization and heteromerization of D₁ and D₃ receptors. According to the synergistic D₁–D₃ intramembrane receptor-receptor interaction, experiments in reserpinized mice showed that D₃ receptor stimulation potentiates D₁ receptor-mediated behavioral effects by a different mechanism than D₂ receptor stimulation. The present study shows that a main functional significance of the D₃ receptor is to obtain a stronger dopaminergic response in the striatal neurons that co-express the two receptors.

Received for publication, December 19, 2007 , and in revised form, July 18, 2008.

^* This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program, National Institute on Drug Abuse, Dept. of Health and Human Services. This work was also supported by the Ministerio de Ciencia y Tecnologia (Grants SAF2006-00170). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: National Institute on Drug Abuse, Intramural Research Program, Dept. of Health and Human Services, 251 Bayview Blvd., Baltimore, MD 21224. Tel.: 410-550-1586; Fax: 443-740-2816; E-mail: sferre{at}intra.nida.nih.gov.

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