Competing G protein-coupled receptor kinases balance G protein and β-arrestin signaling.
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 (AT(1A)R) 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 AT(1A)R, and HEK293 cells expressing other 7TMRs.
BIOS Group, INRA, UMR85, Unité Physiologie de la Reproduction et des Comportements, Nouzilly, France.
Domitille
D
Heitzler
Guillaume
G
Durand
Nathalie
N
Gallay
Aurélien
A
Rizk
Seungkirl
S
Ahn
Jihee
J
Kim
Jonathan D
JD
Violin
Laurence
L
Dupuy
Christophe
C
Gauthier
Vincent
V
Piketty
Pascale
P
Crépieux
Anne
A
Poupon
Frédérique
F
Clément
François
F
Fages
Robert J
RJ
Lefkowitz
Eric
E
Reiter
D019390:Arrestins / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D054770:G-Protein-Coupled Receptor Kinase 3 / Q000378:metabolism; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000378:metabolism; D054768:G-Protein-Coupled Receptor Kinases / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction; D000071557:beta-Arrestins
D019390:Arrestins; D044140:Receptor, Angiotensin, Type 1; D000071557:beta-Arrestins; D054770:G-Protein-Coupled Receptor Kinase 3; C517848:GRK3 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2; D054774:G-Protein-Coupled Receptor Kinase 5; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6; C517898:GRK5 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D019204:GTP-Binding Proteins