Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands
- Departments of aMedicine,
- bBiochemistry, and
- cHoward Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710
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Contributed by Robert J. Lefkowitz, April 24, 2009 (received for review February 13, 2009)
Abstract
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 β-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 β-arrestin2 recruitment, only CCL19 leads to redistribution of β-arrestin2-GFP into endocytic vesicles and classical receptor desensitization. In contrast, these agonists are both capable of signaling through GRK6 and β-arrestin2 to ERK kinases. Thus, this mechanism for “ligand bias” whereby endogenous agonists activate different GRK isoforms leads to functionally distinct pools of β-arrestin.
Footnotes
- 1To whom correspondence should be addressed at: Box 3821, Duke University Medical Center, Durham, NC 27710. E-mail: lefko001{at}receptor-biol.duke.edu
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Author contributions: D.A.Z., J.D.V., E.J.W., and R.J.L. designed research; D.A.Z. performed research; D.A.Z., J.D.V., E.J.W., and R.J.L. analyzed data; and D.A.Z., J.D.V., E.J.W., and R.J.L. wrote the paper.
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The authors declare no conflict of interest.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0904361106/DCSupplemental.
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Freely available online through the PNAS open access option.
