D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 2; pp. 654 - 659
• Main Authors: Rashid, Asim J, So, Christopher H, Kong, Michael M.C, Furtak, Teresa, El-Ghundi, Mufida, Cheng, Regina, O'Dowd, Brian F, George, Susan R
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 09.01.2007; National Acad Sciences
• Subjects: Animals; Biological Sciences; Brain; Cell Line; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Dopamine Agonists - pharmacology; Dopamine Antagonists - pharmacology; GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism; Humans; Kinases; Male; Mice; Mice, Knockout; Neurotransmitters; Protein Structure, Quaternary; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1 - chemistry; Receptors, Dopamine D1 - deficiency; Receptors, Dopamine D1 - genetics; Receptors, Dopamine D1 - metabolism; Receptors, Dopamine D2 - chemistry; Receptors, Dopamine D2 - deficiency; Receptors, Dopamine D2 - genetics; Receptors, Dopamine D2 - metabolism; Signal Transduction
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0604049104

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.