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Biased Signaling of the G-Protein-Coupled Receptor ?₂AR Is Governed by Conformational Exchange Kinetics.

ABSTRACT: G-protein-coupled receptors (GPCRs) mediate a wide range of human physiological functions by transducing extracellular ligand binding events into intracellular responses. GPCRs can activate parallel, independent signaling pathways mediated by G proteins or ?-arrestins. Whereas "balanced" agonists activate both pathways equally, "biased" agonists dominantly activate one pathway, which is of interest for designing GPCR-targeting drugs because it may mitigate undesirable side effects. Previous studies demonstrated that ?-arrestin activation is associated with transmembrane helix VII (TM VII) of GPCRs. Here, single-molecule fluorescence spectroscopy with the ?₂-adrenergic receptor (?₂AR) in the ligand-free state showed that TM VII spontaneously fluctuates between one inactive and one active-like conformation. The presence of the ?-arrestin-biased agonist isoetharine prolongs the dwell time of TM VII in the active-like conformation compared with the balanced agonist formoterol, suggesting that ligands can induce signaling bias by modulating the kinetics of receptor conformational exchange.

SUBMITTER: Lamichhane R

PROVIDER: S-EPMC7213800 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Biased Signaling of the G-Protein-Coupled Receptor β<sub>2</sub>AR Is Governed by Conformational Exchange Kinetics.

Lamichhane Rajan R Liu Jeffrey J JJ White Kate L KL Katritch Vsevolod V Stevens Raymond C RC Wüthrich Kurt K Millar David P DP

Structure (London, England : 1993) 20200123 3

G-protein-coupled receptors (GPCRs) mediate a wide range of human physiological functions by transducing extracellular ligand binding events into intracellular responses. GPCRs can activate parallel, independent signaling pathways mediated by G proteins or β-arrestins. Whereas "balanced" agonists activate both pathways equally, "biased" agonists dominantly activate one pathway, which is of interest for designing GPCR-targeting drugs because it may mitigate undesirable side effects. Previous stud ...[more]

PMID: 31978323

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Project description:Heart failure is the terminal stage of many cardiac diseases, in which β1-adrenoceptor (β1-AR) autoantibody (β1-AA) has a causative role. By continuously activating β1-AR, β1-AA can induce cytotoxicity, leading to cardiomyocyte apoptosis and heart dysfunction. However, the mechanism underlying the persistent activation of β1-AR by β1-AA is not fully understood. Receptor endocytosis has a critical role in terminating signals over time. β2-adrenoceptor (β2-AR) is involved in the regulation of β1-AR signaling. This research aimed to clarify the mechanism of the β1-AA-induced sustained activation of β1-AR and explore the role of the β2-AR/Gi-signaling pathway in this process. The beating frequency of neonatal rat cardiomyocytes, cyclic adenosine monophosphate content, and intracellular Ca2+ levels were examined to detect the activation of β1-AA. Total internal reflection fluorescence microscopy was used to detect the endocytosis of β1-AR. ICI118551 was used to assess β2-AR/Gi function in β1-AR sustained activation induced by β1-AA in vitro and in vivo. Monoclonal β1-AA derived from a mouse hybridoma could continuously activate β1-AR. β1-AA-restricted β1-AR endocytosis, which was reversed by overexpressing the endocytosis scaffold protein β-arrestin1/2, resulting in the cessation of β1-AR signaling. β2-AR could promote β1-AR endocytosis, as demonstrated by overexpressing/interfering with β2-AR in HL-1 cells, whereas β1-AA inhibited the binding of β2-AR to β1-AR, as determined by surface plasmon resonance. ICI118551 biasedly activated the β2-AR/Gi/G protein-coupled receptor kinase 2 (GRK2) pathway, leading to the arrest of limited endocytosis and continuous activation of β1-AR by β1-AA in vitro. In vivo, ICI118551 treatment attenuated myocardial fiber rupture and left ventricular dysfunction in β1-AA-positive mice. This study showed that β1-AA continuously activated β1-AR by inhibiting receptor endocytosis. Biased activation of the β2-AR/Gi/GRK2 signaling pathway could promote β1-AR endocytosis restricted by β1-AA, terminate signal transduction, and alleviate heart damage.

Dataset Information

Biased Signaling of the G-Protein-Coupled Receptor ?₂AR Is Governed by Conformational Exchange Kinetics.

Publications

Biased Signaling of the G-Protein-Coupled Receptor β<sub>2</sub>AR Is Governed by Conformational Exchange Kinetics.

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Biased Signaling of the G-Protein-Coupled Receptor ?2AR Is Governed by Conformational Exchange Kinetics.

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Biased Signaling of the G-Protein-Coupled Receptor β<sub>2</sub>AR Is Governed by Conformational Exchange Kinetics.

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OmicsDI is part of the ELIXIR infrastructure

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Biased Signaling of the G-Protein-Coupled Receptor ?₂AR Is Governed by Conformational Exchange Kinetics.