Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands.
Published
Journal Article
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.
Full Text
Duke Authors
Cited Authors
- Zidar, DA; Violin, JD; Whalen, EJ; Lefkowitz, RJ
Published Date
- June 16, 2009
Published In
Volume / Issue
- 106 / 24
Start / End Page
- 9649 - 9654
PubMed ID
- 19497875
Pubmed Central ID
- 19497875
Electronic International Standard Serial Number (EISSN)
- 1091-6490
Digital Object Identifier (DOI)
- 10.1073/pnas.0904361106
Language
- eng
Conference Location
- United States