Dual agonist occupancy of AT1-R–α2C-AR heterodimers results in atypical Gs-PKA signaling View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-04

AUTHORS

Morgane Bellot, Ségolène Galandrin, Cédric Boularan, Heinrich J Matthies, Fabien Despas, Colette Denis, Jonathan Javitch, Serge Mazères, Samra Joke Sanni, Véronique Pons, Marie-Hélène Seguelas, Jakob L Hansen, Atul Pathak, Aurelio Galli, Jean-Michel Sénard, Céline Galés

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. More... »

PAGES

271-279

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nchembio.1766

DOI

http://dx.doi.org/10.1038/nchembio.1766

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1044052701

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/25706338


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452 schema:name Center for Molecular Recognition and Departments of Psychiatry and Pharmacology, Columbia University, New York, New York, USA.
453 College of Physicians and Surgeons, Columbia University, New York, New York, USA.
454 Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York, USA.
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456 https://www.grid.ac/institutes/grid.425956.9 schema:alternateName Novo Nordisk (Denmark)
457 schema:name Department of Clinical Biochemistry, Glostrup Hospital, Glostrup, Denmark.
458 Diabetes Biology and Metabolism, Novo Nordisk, Måløv, Denmark.
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460 https://www.grid.ac/institutes/grid.461904.e schema:alternateName Institute of Pharmacology and Structural Biology
461 schema:name Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS, UMR 508, Université Toulouse III Paul Sabatier, Toulouse, France.
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463 https://www.grid.ac/institutes/grid.462178.e schema:alternateName Institute of Cardiovascular and Metabolic Diseases
464 schema:name Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, U1048, Université Toulouse III Paul Sabatier, Toulouse, France.
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