D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum.
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.
Rashid
Asim J
AJ
Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
So
Christopher H
CH
Kong
Michael M C
MM
Furtak
Teresa
T
El-Ghundi
Mufida
M
Cheng
Regina
R
O'Dowd
Brian F
BF
George
Susan R
SR
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
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D043802:GTP-Binding Protein alpha Subunits, Gq-G11