title: D1 and D2 dopamine receptors form heterooligomers and cointernalize after selective activation of either receptor.
abstract: We provided evidence for the formation of a novel phospholipase C-mediated calcium signal arising from coactivation of D1 and D2 dopamine receptors. In the present study, robust fluorescence resonance energy transfer showed that these receptors exist in close proximity indicative of D1-D2 receptor heterooligomerization. The close proximity of these receptors within the heterooligomer allowed for cross-phosphorylation of the D2 receptor by selective activation of the D1 receptor. D1-D2 receptor heterooligomers were internalized when the receptors were coactivated by dopamine or either receptor was singly activated by the D1-selective agonist (+/-)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) or the D2-selective agonist quinpirole. The D2 receptor expressed alone did not internalize after activation by quinpirole except when coexpressed with the D1 receptor. D1-D2 receptor heterooligomerization resulted in an altered level of steady-state cell surface expression compared with D1 and D2 homooligomers, with increased D2 and decreased D1 receptor cell surface density. Together, these results demonstrated that D1 and D2 receptors formed heterooligomeric units with unique cell surface localization, internalization, and transactivation properties that are distinct from that of D1 and D2 receptor homooligomers.
authors.affiliation: Departments of Pharmacology and Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: So
authors.forename: George
authors.initials: G
authors.lastname: Varghese
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Curley
authors.forename: Michael M C
authors.initials: MM
authors.lastname: Kong
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alijaniaram
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Ji
authors.forename: Tuan
authors.initials: T
authors.lastname: Nguyen
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; D001704:Biopolymers; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D004705:Endocytosis; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D018613:Microscopy, Confocal; D011869:Radioligand Assay; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism
chemical_list: D001704:Biopolymers; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2