D1–D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum
- Asim J. Rashid*,†,
- Christopher H. So*,
- Michael M. C. Kong*,
- Teresa Furtak*,
- Mufida El-Ghundi*,
- Regina Cheng†,
- Brian F. O'Dowd*,†, and
- Susan R. George*,†,‡,§
- Departments of *Pharmacology and
- ‡Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8; and
- †Centre for Addiction and Mental Health, Toronto, Ontario, Canada M5T 1R8
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Edited by Robert J. Lefkowitz, Duke University Medical Center, Durham, NC, and approved November 9, 2006 (received for review May 17, 2006)
Abstract
We demonstrate a heteromeric D1–D2 dopamine receptor signaling complex in brain that is coupled to Gq/11 and requires agonist binding to both receptors for G protein activation and intracellular calcium release. The D1 agonist SKF83959 was identified as a specific agonist for the heteromer that activated Gq/11 by functioning as a full agonist for the D1 receptor and a high-affinity partial agonist for a pertussis toxin-resistant D2 receptor within the complex. We provide evidence that the D1–D2 signaling complex can be more readily detected in mice that are 8 months in age compared with animals that are 3 months old, suggesting that calcium signaling through the D1–D2 dopamine receptor complex is relevant for function in the postadolescent brain. Activation of Gq/11 through the heteromer increases levels of calcium/calmodulin-dependent protein kinase IIα in the nucleus accumbens, unlike activation of Gs/olf-coupled D1 receptors, indicating a mechanism by which D1–D2 dopamine receptor complexes may contribute to synaptic plasticity.
Footnotes
- §To whom correspondence should be addressed at: Department of Pharmacology, University of Toronto, MSB Room 4358, Toronto, ON, Canada M5S 1A8. E-mail: s.george{at}utoronto.ca
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Author contributions: B.F.O. and S.R.G. contributed equally to this paper; A.J.R., C.H.S., M.M.C.K., and S.R.G. designed research; A.J.R., C.H.S., M.M.C.K., T.F., and R.C. performed research; M.E.-G. contributed new reagents/analytic tools; A.J.R., C.H.S., M.M.C.K., T.F., B.F.O., and S.R.G. analyzed data; and A.J.R., B.F.O., and S.R.G. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS direct submission.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0604049104/DC1.
- Abbreviations:
- AC,
- adenylyl cyclase;
- CaMKIIα,
- calcium/calmodulin-dependent protein kinase IIα;
- GTPγS,
- guanosine 5′-γ-thiotriphosphate;
- IP3,
- inositol trisphosphate;
- PLC,
- phospholipase C;
- PTX,
- pertussis toxin.
- © 2006 by The National Academy of Sciences of the USA
