title: Calcium signaling by dopamine D5 receptor and D5-D2 receptor hetero-oligomers occurs by a mechanism distinct from that for dopamine D1-D2 receptor hetero-oligomers.
abstract: In this report, we investigated whether the D5 dopamine receptor, given its structural and sequence homology with the D1 receptor, could interact with the D2 receptor to mediate a calcium signal similar to the G(q/11) protein-linked phospholipase C-mediated calcium signal resulting from the coactivation of D1 and D2 dopamine receptors within D1-D2 receptor heterooligomers. Fluorescent resonance energy transfer experiments demonstrated close colocalization of cell surface D5 and D2 receptors (<100 A), indicating hetero-oligomerization of D5 and D2 receptors in cells coexpressing both receptors. Coactivation of D5 and D2 receptors within the D5-D2 hetero-oligomers activated a calcium signal. However, unlike what is observed for D1 receptors, which activate extensive calcium mobilization only within a complex with the D2 receptors, a robust calcium signal was triggered by D5 receptors expressed alone. Hetero-oligomerization with the D2 receptor attenuated the ability of the D5 receptor to trigger a calcium signal. The D5 and D5-D2-associated calcium signals were G(q/11) protein-linked and phospholipase C-mediated but were also critically dependent on the influx of extracellular calcium through store-operated calcium channels, unlike the calcium release triggered by D1-D2 heterooligomers. Collectively, these results demonstrate that calcium signaling through D5-D2 receptor hetero-oligomers occurred through a distinct mechanism to achieve an increase in intracellular calcium levels.
authors.affiliation: Department of Pharmacology, University of Toronto, and the Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: So
authors.forename: Vaneeta
authors.initials: V
authors.lastname: Verma
authors.forename: Mohammad
authors.initials: M
authors.lastname: Alijaniaram
authors.forename: Regina
authors.initials: R
authors.lastname: Cheng
authors.forename: Asim J
authors.initials: AJ
authors.lastname: Rashid
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; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D018492:Dopamine Antagonists / Q000737:chemistry; D065127:Dopamine D2 Receptor Antagonists; D005110:Extracellular Space / Q000737:chemistry / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000737:chemistry / Q000502:physiology; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000502:physiology*; D050641:Receptors, Dopamine D5 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D010738:Type C Phospholipases / Q000737:chemistry / Q000502:physiology
chemical_list: D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050641:Receptors, Dopamine D5; D010738:Type C Phospholipases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D002118:Calcium