title: D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum.
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 IIalpha 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.
authors.affiliation: Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Asim J
authors.initials: AJ
authors.lastname: Rashid
authors.forename: Christopher H
authors.initials: CH
authors.lastname: So
authors.forename: Michael M C
authors.initials: MM
authors.lastname: Kong
authors.forename: Teresa
authors.initials: T
authors.lastname: Furtak
authors.forename: Mufida
authors.initials: M
authors.lastname: El-Ghundi
authors.forename: Regina
authors.initials: R
authors.lastname: Cheng
authors.forename: Brian F
authors.initials: BF
authors.lastname: O'Dowd
authors.forename: Susan R
authors.initials: SR
authors.lastname: George
mesh_terms: D000818:Animals; D002460:Cell Line; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020836:Protein Structure, Quaternary; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D043802:GTP-Binding Protein alpha Subunits, Gq-G11