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J. Biol. Chem., Vol. 279, Issue 34, 35671-35678, August 20, 2004

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Dopamine D1 and D2 Receptor Co-activation Generates a Novel Phospholipase C-mediated Calcium Signal^*

Samuel P. Lee, Christopher H. So, Asim J. Rashid¶||, George Varghese, Regina Cheng, A. José Lança, Brian F. O'Dowd¶, and Susan R. George¶**

From the Departments of Pharmacology and ^**Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada and the ^¶Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada

Although dopamine D1 and D2 receptors belong to distinct subfamilies of dopamine receptors, several lines of evidence indicate that they are functionally linked. However, a mechanism for this linkage has not been elucidated. In this study, we demonstrate that agonist stimulation of co-expressed D1 and D2 receptors resulted in an increase of intracellular calcium levels via a signaling pathway not activated by either receptor alone or when only one of the co-expressed receptors was activated by a selective agonist. Calcium signaling by D1-D2 receptor co-activation was abolished following treatment with a phospholipase C inhibitor but not with pertussis toxin or inhibitors of protein kinase A or protein kinase C, indicating coupling to the G_q pathway. We also show, by co-immunoprecipitation from rat brain and from cells co-expressing the receptors, that D1 and D2 receptors are part of the same heteromeric protein complex and, by immunohistochemistry, that these receptors are co-expressed and co-localized within neurons of human and rat brain. This demonstration that D1 and D2 receptors have a novel cellular function when co-activated in the same cell represents a significant step toward elucidating the mechanism of the functional link observed between these two receptors in brain.

Received for publication, February 22, 2004 , and in revised form, May 19, 2004.

^* This work was supported by grants from the National Institute on Drug Abuse and from the Canadian Institutes of Health Research. 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.

These two authors contributed equally to this work.

^|| Supported by a Fellowship from the Centre for Addiction and Mental Health.

Holder of a Canada Research Chair in Molecular Neuroscience. To whom correspondence should be addressed: Rm. 4358, Medical Sciences Bldg., 1 King's College Circle, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Tel.: 416-978-3367; Fax: 416-971-2868; E-mail: s.george{at}utoronto.ca.

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