Competing G protein‐coupled receptor kinases balance G protein and β‐arrestin signaling

Competing G protein‐coupled receptor kinases balance G protein and β‐arrestin signaling

Abstract Seven‐transmembrane receptors (7TMRs) are involved in nearly all aspects of chemical communications and represent major drug targets. 7TMRs transmit their signals not only via heterotrimeric G proteins but also through β‐arrestins, whose recruitment to the activated receptor is regulated by...

Full description

Saved in:
Bibliographic Details
Main Authors: Domitille Heitzler, Guillaume Durand, Nathalie Gallay, Aurélien Rizk, Seungkirl Ahn, Jihee Kim, Jonathan D Violin, Laurence Dupuy, Christophe Gauthier, Vincent Piketty, Pascale Crépieux, Anne Poupon, Frédérique Clément, François Fages, Robert J Lefkowitz, Eric Reiter
Format: Article
Language:English
Published: Springer Nature 2012-06-01
Series:Molecular Systems Biology
Subjects:
β‐arrestin
7 transmembrane receptors
dynamical modeling
G protein
signal transduction
Online Access:https://doi.org/10.1038/msb.2012.22
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract Seven‐transmembrane receptors (7TMRs) are involved in nearly all aspects of chemical communications and represent major drug targets. 7TMRs transmit their signals not only via heterotrimeric G proteins but also through β‐arrestins, whose recruitment to the activated receptor is regulated by G protein‐coupled receptor kinases (GRKs). In this paper, we combined experimental approaches with computational modeling to decipher the molecular mechanisms as well as the hidden dynamics governing extracellular signal‐regulated kinase (ERK) activation by the angiotensin II type 1A receptor (AT1AR) in human embryonic kidney (HEK)293 cells. We built an abstracted ordinary differential equations (ODE)‐based model that captured the available knowledge and experimental data. We inferred the unknown parameters by simultaneously fitting experimental data generated in both control and perturbed conditions. We demonstrate that, in addition to its well‐established function in the desensitization of G‐protein activation, GRK2 exerts a strong negative effect on β‐arrestin‐dependent signaling through its competition with GRK5 and 6 for receptor phosphorylation. Importantly, we experimentally confirmed the validity of this novel GRK2‐dependent mechanism in both primary vascular smooth muscle cells naturally expressing the AT1AR, and HEK293 cells expressing other 7TMRs.
ISSN:1744-4292

Similar Items