Dataset Information

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

ABSTRACT: Most G protein-coupled receptors (GPCRs) signal through both heterotrimeric G proteins and ?-arrestins (?arr1 and ?arr2). Although synthetic ligands can elicit biased signaling by G protein- vis-à-vis ?arr-mediated transduction, endogenous mechanisms for biasing signaling remain elusive. Here we report that S-nitrosylation of a novel site within ?arr1/2 provides a general mechanism to bias ligand-induced signaling through GPCRs by selectively inhibiting ?arr-mediated transduction. Concomitantly, S-nitrosylation endows cytosolic ?arrs with receptor-independent function. Enhanced ?arr S-nitrosylation characterizes inflammation and aging as well as human and murine heart failure. In genetically engineered mice lacking ?arr2-Cys253 S-nitrosylation, heart failure is exacerbated in association with greatly compromised ?-adrenergic chronotropy and inotropy, reflecting ?arr-biased transduction and ?-adrenergic receptor downregulation. Thus, S-nitrosylation regulates ?arr 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.

SUBMITTER: Hayashi H

PROVIDER: S-EPMC5940012 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Publications

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

Hayashi Hiroki H Hess Douglas T DT Zhang Rongli R Sugi Keiki K Gao Huiyun H Tan Bea L BL Bowles Dawn E DE Milano Carmelo A CA Jain Mukesh K MK Koch Walter J WJ Stamler Jonathan S JS

Molecular cell 20180501 3

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, ...[more]

PMID: 29727618

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Project description:Chemokines are essential for guiding cell migration. Atypical chemokine receptors (ACKRs) contribute to the cell migration process by binding, internalizing and degrading local chemokines, which enables the formation of confined gradients. ACKRs are heptahelical membrane spanning molecules structurally related to G-protein coupled receptors (GPCRs), but seem to be unable to signal through G-proteins upon ligand binding. ACKR4 internalizes the chemokines CCL19, CCL21, and CCL25 and is best known for shaping functional CCL21 gradients. Ligand binding to ACKR4 has been shown to recruit β-arrestins that has led to the assumption that chemokine scavenging relies on β-arrestin-mediated ACKR4 trafficking, a common internalization route taken by class A GPCRs. Here, we show that CCL19, CCL21, and CCL25 readily recruited β-arrestin1 and β-arrestin2 to human ACKR4, but found no evidence for β-arrestin-dependent or independent ACKR4-mediated activation of the kinases Erk1/2, Akt, or Src. However, we demonstrate that β-arrestins interacted with ACKR4 in the steady-state and contributed to the spontaneous trafficking of the receptor in the absence of chemokines. Deleting the C-terminus of ACKR4 not only interfered with the interaction of β-arrestins, but also with the uptake of fluorescently labeled cognate chemokines. We identify the GPCR kinase GRK3, and to a lesser extent GRK2, but not GRK4, GRK5, and GRK6, to be recruited to chemokine-stimulated ACKR4. We show that GRK3 recruitment proceded the recruitment of β-arrestins upon ACKR4 engagement and that GRK2/3 inhibition partially interfered with steady-state interaction and chemokine-driven recruitment of β-arrestins to ACKR4. Overexpressing β-arrestin2 accelerated the uptake of fluorescently labeled CCL19, indicating that β-arrestins contribute to the chemokine scavenging activity of ACKR4. By contrast, cells lacking β-arrestins were still capable to take up fluorescently labeled CCL19 demonstrating that β-arrestins are dispensable for chemokine scavenging by ACKR4.

Dataset Information

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

Publications

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

Similar Datasets

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