Different G protein-coupled receptor kinases govern G protein and β-arrestin-mediated signaling of V2 vasopressin receptor
Abstract
Signaling through β-arrestins is a recently appreciated mechanism used by seven-transmembrane receptors. Because G protein-coupled receptor kinase (GRK) phosphorylation of such receptors is generally a prerequisite for β-arrestin binding, we studied the roles of different GRKs in promoting β-arrestin-mediated extracellular signal-regulated kinase (ERK) activation by a typical seven-transmembrane receptor, the Gs-coupled V2 vasopressin receptor. Gs- and β-arrestin-mediated pathways to ERK activation could be distinguished with H89, an inhibitor of protein kinase A, and β-arrestin 2 small interfering RNA, respectively. The roles of GRK2, -3, -5, and -6 were assessed by suppressing their expression with specific small interfering RNA sequences. By using this approach, we demonstrated that GRK2 and -3 are responsible for most of the agonist-dependent receptor phosphorylation, desensitization, and recruitment of β-arrestins. In contrast, GRK5 and -6 mediated much less receptor phosphorylation and β-arrestin recruitment, but yet appeared exclusively to support β-arrestin 2-mediated ERK activation. GRK2 suppression actually increased β-arrestin-stimulated ERK activation. These results suggest that β-arrestin recruited in response to receptor phosphorylation by different GRKs has distinct functional potentials.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- February 2005
- DOI:
- 10.1073/pnas.0409534102
- Bibcode:
- 2005PNAS..102.1448R
- Keywords:
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- CELL BIOLOGY