Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands.
CCL19 and CCL21 are endogenous agonists for the seven-transmembrane receptor CCR7. They are equally active in promoting G protein stimulation and chemotaxis. Yet, we find that they result in striking differences in activation of the G protein-coupled receptor kinase (GRK)/ss-arrestin system. CCL19 leads to robust CCR7 phosphorylation and beta-arrestin2 recruitment catalyzed by both GRK3 and GRK6 whereas CCL21 activates GRK6 alone. This differential GRK activation leads to distinct functional consequences. Although each ligand leads to beta-arrestin2 recruitment, only CCL19 leads to redistribution of beta-arrestin2-GFP into endocytic vesicles and classical receptor desensitization. In contrast, these agonists are both capable of signaling through GRK6 and beta-arrestin2 to ERK kinases. Thus, this mechanism for "ligand bias" whereby endogenous agonists activate different GRK isoforms leads to functionally distinct pools of beta-arrestin.
Zidar
David A
DA
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Violin
Jonathan D
JD
Whalen
Erin J
EJ
Lefkowitz
Robert J
RJ
D019390:Arrestins / Q000378:metabolism; D002460:Cell Line; D054768:G-Protein-Coupled Receptor Kinases / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D034741:RNA, Small Interfering; D054400:Receptors, CCR7 / Q000378:metabolism; D015398:Signal Transduction; D000071557:beta-Arrestins
D019390:Arrestins; C515370:CCR7 protein, human; D008024:Ligands; D034741:RNA, Small Interfering; D054400:Receptors, CCR7; D000071557:beta-Arrestins; D054768:G-Protein-Coupled Receptor Kinases; D020928:Mitogen-Activated Protein Kinases