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Mol Cell. 2018 May 3;70(3):473-487.e6. doi: 10.1016/j.molcel.2018.03.034.

S-Nitrosylation of β-Arrestins Biases Receptor Signaling and Confers Ligand Independence.

Author information

1
Institute for Transformative Molecular Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
2
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Case Cardiovascular Research Institute, Case Western University School of Medicine, Cleveland, OH 44106, USA; Harrington Heart and Vascular Institute, Case Western University School of Medicine, Cleveland, OH 44106, USA.
3
Institute for Transformative Molecular Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
4
Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
5
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Case Cardiovascular Research Institute, Case Western University School of Medicine, Cleveland, OH 44106, USA; Harrington Heart and Vascular Institute, Case Western University School of Medicine, Cleveland, OH 44106, USA; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA.
6
Department of Medicine and Center for Translational Research, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
7
Institute for Transformative Molecular Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA. Electronic address: jonathan.stamler@case.edu.

Abstract

Most G protein-coupled receptors (GPCRs) signal through both heterotrimeric G proteins and β-arrestins (βarr1 and βarr2). Although synthetic ligands can elicit biased signaling by G protein- vis-à-vis βarr-mediated transduction, endogenous mechanisms for biasing signaling remain elusive. Here we report that S-nitrosylation of a novel site within βarr1/2 provides a general mechanism to bias ligand-induced signaling through GPCRs by selectively inhibiting βarr-mediated transduction. Concomitantly, S-nitrosylation endows cytosolic βarrs with receptor-independent function. Enhanced βarr S-nitrosylation characterizes inflammation and aging as well as human and murine heart failure. In genetically engineered mice lacking βarr2-Cys253 S-nitrosylation, heart failure is exacerbated in association with greatly compromised β-adrenergic chronotropy and inotropy, reflecting βarr-biased transduction and β-adrenergic receptor downregulation. Thus, S-nitrosylation regulates βarr function and, thereby, biases transduction through GPCRs, demonstrating a novel role for nitric oxide in cellular signaling with potentially broad implications for patho/physiological GPCR function, including a previously unrecognized role in heart failure.

KEYWORDS:

G protein-coupled receptor; GPCR bias; S-nitrosylation; angiotensin receptor; arrestin; heart failure; nitric oxide; nitric oxide synthase; β-adrenergic receptor; β-arrestin dimerization

PMID:
29727618
PMCID:
PMC5940012
DOI:
10.1016/j.molcel.2018.03.034
[Indexed for MEDLINE]
Free PMC Article

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