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Nat Chem Biol. 2015 Apr;11(4):271-9. doi: 10.1038/nchembio.1766. Epub 2015 Feb 23.

Dual agonist occupancy of AT1-R-α2C-AR heterodimers results in atypical Gs-PKA signaling.

Author information

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
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
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.
4
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.
5
Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS, UMR 508, Université Toulouse III Paul Sabatier, Toulouse, France.
6
1] Department of Clinical Biochemistry, Glostrup Hospital, Glostrup, Denmark. [2] Diabetes Biology and Metabolism, Novo Nordisk, Måløv, Denmark.
7
Diabetes Biology and Metabolism, Novo Nordisk, Måløv, Denmark.
8
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.

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.

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PMID:
25706338
PMCID:
PMC4465922
DOI:
10.1038/nchembio.1766
[Indexed for MEDLINE]
Free PMC Article

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