Functional antagonism of different G protein-coupled receptor kinases for beta-arrestin-mediated angiotensin II receptor signaling.
beta-arrestins bind to G protein-coupled receptor kinase (GRK)-phosphorylated seven transmembrane receptors, desensitizing their activation of G proteins, while concurrently mediating receptor endocytosis, and some aspects of receptor signaling. We have used RNA interference to assess the roles of the four widely expressed isoforms of GRKs (GRK 2, 3, 5, and 6) in regulating beta-arrestin-mediated signaling to the mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK) 1/2 by the angiotensin II type 1A receptor. Angiotensin II-stimulated receptor phosphorylation, beta-arrestin recruitment, and receptor endocytosis are all mediated primarily by GRK2/3. In contrast, inhibiting GRK 5 or 6 expression abolishes beta-arrestin-mediated ERK activation, whereas lowering GRK 2 or 3 leads to an increase in this signaling. Consistent with these findings, beta-arrestin-mediated ERK activation is enhanced by overexpression of GRK 5 and 6, and reciprocally diminished by GRK 2 and 3. These findings indicate distinct functional capabilities of beta-arrestins bound to receptors phosphorylated by different classes of GRKs.
Kim
Jihee
J
Department of Medicine, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
Ahn
Seungkirl
S
Ren
Xiu-Rong
XR
Whalen
Erin J
EJ
Reiter
Eric
E
Wei
Huijun
H
Lefkowitz
Robert J
RJ
D019390:Arrestins / Q000502:physiology; D002460:Cell Line; D016895:Culture Media, Serum-Free; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics; D054771:G-Protein-Coupled Receptor Kinase 4; D054774:G-Protein-Coupled Receptor Kinase 5; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney; D007700:Kinetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011945:Receptors, Angiotensin / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection; D051552:beta-Adrenergic Receptor Kinases; D000071557:beta-Arrestins
D019390:Arrestins; D016895:Culture Media, Serum-Free; D034741:RNA, Small Interfering; D011945:Receptors, Angiotensin; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; D020794:Receptor Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D054771:G-Protein-Coupled Receptor Kinase 4; D054774:G-Protein-Coupled Receptor Kinase 5; C517855:GRK4 protein, human; C517898:GRK5 protein, human; D048052:Mitogen-Activated Protein Kinase 3