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G protein–coupled receptors: from radioligand binding to cellular signaling
Howard A. Rockman, Robert J. Lefkowitz
Howard A. Rockman, Robert J. Lefkowitz
Published March 1, 2024
Citation Information: J Clin Invest. 2024;134(5):e178109. https://doi.org/10.1172/JCI178109.
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100th Anniversary Viewpoints Article has an altmetric score of 35

G protein–coupled receptors: from radioligand binding to cellular signaling

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Abstract

Authors

Howard A. Rockman, Robert J. Lefkowitz

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Figure 1

Current concepts in GPCR signaling.

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Current concepts in GPCR signaling.
(A) The binding of norepinephrine to...
(A) The binding of norepinephrine to the orthosteric site of the βAR leads to the formation of a high-affinity ternary complex composed of agonist, βAR, and heterotrimeric G protein (including Gα, Gβ, and Gγ). Competitive radioligand-binding assays show shifted curves in the presence of G protein (Gs). A leftward curve shift indicates allosteric cooperativity and stabilization of a high-affinity receptor conformation. The high-affinity ternary complex stimulates G protein–mediated cAMP accumulation and intracellular signaling. As a physiological consequence, heart rate and contractility increase. β-Arrestins are recruited to agonist-occupied GPCR kinase (GRK) phosphorylated receptors to turn off, or desensitize, the G protein signal by sterically preventing G protein binding. β-Arrestin also stabilizes a high-affinity conformation of the βAR, as reflected by the leftward shift in the competition radioligand binding curve. β-Arrestin mediates receptor endocytosis and functions as a scaffold for many signaling proteins, thereby activating a suite of distinct β-arrestin–dependent signaling pathways. β-Arrestin–mediated signaling can occur inside the cell, initiated by the internalized receptor–β-arrestin complex, or at the plasma membrane via EGFR transactivation and ERK activation. Notably, the transactivation pathway is cardioprotective. (B) Biased signaling is a process whereby alternate GPCR ligands preferentially stimulate cellular pathways through differential engagement of a transducer, either G proteins or β arrestins, leading to distinct signaling profiles.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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