title: Angiotensin II type I and prostaglandin F2α receptors cooperatively modulate signaling in vascular smooth muscle cells.
abstract: The angiotensin II type I (AT1R) and the prostaglandin F2α (PGF2α) F prostanoid (FP) receptors are both potent regulators of blood pressure. Physiological interplay between AT1R and FP has been described. Abdominal aortic ring contraction experiments revealed that PGF2α-dependent activation of FP potentiated angiotensin II-induced contraction, whereas FP antagonists had the opposite effect. Similarly, PGF2α-mediated vasoconstriction was symmetrically regulated by co-treatment with AT1R agonist and antagonist. The underlying canonical Gαq signaling via production of inositol phosphates mediated by each receptor was also regulated by antagonists for the other receptor. However, binding to their respective agonists, regulation of receptor-mediated MAPK activation and vascular smooth muscle cell growth were differentially or asymmetrically regulated depending on how each of the two receptors were occupied by either agonist or antagonist. Physical interactions between these receptors have never been reported, and here we show that AT1R and FP form heterodimeric complexes in both HEK 293 and vascular smooth muscle cells. These findings imply that formation of the AT1R/FP dimer creates a novel allosteric signaling unit that shows symmetrical and asymmetrical signaling behavior, depending on the outcome measured. AT1R/FP dimers may thus be important in the regulation of blood pressure.
authors.affiliation: From the Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6.
authors.forename: Eugénie
authors.initials: E
authors.lastname: Goupil
authors.affiliation: From the Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6.
authors.forename: Dany
authors.initials: D
authors.lastname: Fillion
authors.affiliation: From the Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Clément
authors.affiliation: the Centre de Recherche, Institut de Cardiologie de Montréal, Montréal, Québec H1T 1C8, Canada.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Luo
authors.affiliation: From the Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6.
authors.forename: Dominic
authors.initials: D
authors.lastname: Devost
authors.affiliation: From the Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6.
authors.forename: Rory
authors.initials: R
authors.lastname: Sleno
authors.affiliation: From the Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6.
authors.forename: Darlaine
authors.initials: D
authors.lastname: Pétrin
authors.affiliation: From the Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6, the Lady Davis Institute, Montréal Jewish General Hospital, Montréal, Québec H3T 1E2, and.
authors.forename: H Uri
authors.initials: HU
authors.lastname: Saragovi
authors.affiliation: the Centre de Recherche, Institut de Cardiologie de Montréal, Montréal, Québec H1T 1C8, Canada.
authors.forename: Éric
authors.initials: É
authors.lastname: Thorin
authors.affiliation: From the Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6, the Department of Medicine, McGill University Health Center Research Institute, Montréal, Québec H3A 2B2, the Department of Anatomy and Cell Biology, McGill University, Montréal, Québec H3A 0CT, stephane.laporte@mcgill.ca.
authors.forename: Stéphane A
authors.initials: SA
authors.lastname: Laporte
authors.affiliation: From the Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6, terence.hebert@mcgill.ca.
authors.forename: Terence E
authors.initials: TE
authors.lastname: Hébert
mesh_terms: D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D044140:Receptor, Angiotensin, Type 1; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor
keywords: Allosteric Regulation; Angiotensin II; Dimerization; G Protein; G Protein-coupled Receptor (GPCR); Prostaglandin