Dopamine D1 and D2 receptor Co-activation generates a novel phospholipase C-mediated calcium signal.
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.
Lee
Samuel P
SP
Department of Pharmacology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
So
Christopher H
CH
Rashid
Asim J
AJ
Varghese
George
G
Cheng
Regina
R
Lança
A José
AJ
O'Dowd
Brian F
BF
George
Susan R
SR
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D018491:Dopamine Agonists / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D011760:Pyrrolidinones / Q000494:pharmacology; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D020239:Receptor Cross-Talk; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D001552:Benzazepines; D018491:Dopamine Agonists; D004963:Estrenes; D011760:Pyrrolidinones; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D019257:Quinpirole; C067113:SK&F 81297; D010738:Type C Phospholipases; D002118:Calcium