Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 5, Pages 1448-1453Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0409534102
Keywords
extracellular signal-regulated kinase phosphorylation; desensitization; small interfering RNA
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Funding
- NHLBI NIH HHS [R01 HL16037, HL 70631, R01 HL070631, R01 HL016037] Funding Source: Medline
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Signaling through beta-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 beta-arrestin binding, we studied the roles of different GRKs in promoting P-arrestin-mediated extracellular signal-regulated kinase (ERK) activation by a typical seven-transmembrane receptor, the Gs-coupled V2 vasopressin receptor. Gs- and beta-arrestin-mediated pathways to ERK activation could be distinguished with H89, an inhibitor of protein kinase A, and beta-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 beta-arrestins. In contrast, GRK5 and -6 mediated much less receptor phosphorylation and P-arrestin recruitment, but yet appeared exclusively to support beta-arrestin 2-mediated ERK activation. GRK2 suppression actually increased beta-arrestin-stimulated ERK activation. These results suggest that P-arrestin recruited in response to receptor phosphorylation by different GRKs has distinct functional potentials.
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