title: Dual agonist occupancy of AT1-R-α2C-AR heterodimers results in atypical Gs-PKA signaling.
abstract: Hypersecretion of norepinephrine (NE) and angiotensin II (AngII) is a hallmark of major prevalent cardiovascular diseases that contribute to cardiac pathophysiology and morbidity. Herein, we explore whether heterodimerization of presynaptic AngII AT1 receptor (AT1-R) and NE α2C-adrenergic receptor (α2C-AR) could underlie their functional cross-talk to control NE secretion. Multiple bioluminescence resonance energy transfer and protein complementation assays allowed us to accurately probe the structures and functions of the α2C-AR-AT1-R dimer promoted by ligand binding to individual protomers. We found that dual agonist occupancy resulted in a conformation of the heterodimer different from that induced by active individual protomers and triggered atypical Gs-cAMP-PKA signaling. This specific pharmacological signaling unit was identified in vivo to promote not only NE hypersecretion in sympathetic neurons but also sympathetic hyperactivity in mice. Thus, we uncovered a new process by which GPCR heterodimerization creates an original functional pharmacological entity and that could constitute a promising new target in cardiovascular therapeutics.
authors.affiliation: Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, U1048, Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Morgane
authors.initials: M
authors.lastname: Bellot
authors.affiliation: Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, U1048, Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Ségolène
authors.initials: S
authors.lastname: Galandrin
authors.affiliation: Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, U1048, Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Boularan
authors.affiliation: 1] Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. [2] Neuroscience Program in Substance Abuse, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Heinrich J
authors.initials: HJ
authors.lastname: Matthies
authors.affiliation: 1] Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, U1048, Université Toulouse III Paul Sabatier, Toulouse, France. [2] Service de Pharmacologie Clinique, Centre Hospitalier Universitaire de Toulouse, Faculté de Médecine, Toulouse, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Despas
authors.affiliation: Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, U1048, Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Colette
authors.initials: C
authors.lastname: Denis
authors.affiliation: 1] Center for Molecular Recognition and Departments of Psychiatry and Pharmacology, Columbia University, New York, New York, USA. [2] College of Physicians and Surgeons, Columbia University, New York, New York, USA. [3] Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Javitch
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS, UMR 508, Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Mazères
authors.affiliation: 1] Department of Clinical Biochemistry, Glostrup Hospital, Glostrup, Denmark. [2] Diabetes Biology and Metabolism, Novo Nordisk, Måløv, Denmark.
authors.forename: Samra Joke
authors.initials: SJ
authors.lastname: Sanni
authors.affiliation: Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, U1048, Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Pons
authors.affiliation: Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, U1048, Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Seguelas
authors.affiliation: Diabetes Biology and Metabolism, Novo Nordisk, Måløv, Denmark.
authors.forename: Jakob L
authors.initials: JL
authors.lastname: Hansen
authors.affiliation: 1] Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, U1048, Université Toulouse III Paul Sabatier, Toulouse, France. [2] Service de Pharmacologie Clinique, Centre Hospitalier Universitaire de Toulouse, Faculté de Médecine, Toulouse, France.
authors.forename: Atul
authors.initials: A
authors.lastname: Pathak
authors.affiliation: 1] Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. [2] Neuroscience Program in Substance Abuse, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. [3] Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. [4] Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Galli
authors.affiliation: 1] Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, U1048, Université Toulouse III Paul Sabatier, Toulouse, France. [2] Service de Pharmacologie Clinique, Centre Hospitalier Universitaire de Toulouse, Faculté de Médecine, Toulouse, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Sénard
authors.affiliation: Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, U1048, Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Galés
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000737:chemistry; D000818:Animals; D001703:Biophysics; D002318:Cardiovascular Diseases / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D019281:Dimerization; D015195:Drug Design; D019204:GTP-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D009638:Norepinephrine / Q000737:chemistry; D016716:PC12 Cells; D010766:Phosphorylation; D011487:Protein Conformation; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists*; D018341:Receptors, Adrenergic, alpha-2 / Q000737:chemistry; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000187:drug effects
chemical_list: D000316:Adrenergic alpha-Agonists; D008024:Ligands; D044140:Receptor, Angiotensin, Type 1; D018341:Receptors, Adrenergic, alpha-2; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D009638:Norepinephrine