Functional antagonism of different G protein-coupled receptor kinases for β-arrestin-mediated angiotensin II receptor signaling

Jihee Kim, Seungkirl Ahn, Xiu Rong Ren, Erin J. Whalen, Eric Reiter, Huijun Wei, Robert J. Lefkowitz

Research output: Contribution to journalArticlepeer-review

Abstract

β-arrestins bind to G protein-coupled receptor kinase (GRK)-phosphorylated seven transmembrane receptors, desensitizing their activation of G proteins, while concurrently mediating receptor endocytosis, and some aspects of receptor signaling. We have used RNA interference to assess the roles of the four widely expressed isoforms of GRKs (GRK 2, 3, 5, and 6) in regulating β-arrestin-mediated signaling to the mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK) 1/2 by the angiotensin II type 1A receptor. Angiotensin II-stimulated receptor phosphorylation, β-arrestin recruitment, and receptor endocytosis are all mediated primarily by GRK2/3. In contrast, inhibiting GRK 5 or 6 expression abolishes β-arrestin-mediated ERK activation, whereas lowering GRK 2 or 3 leads to an increase in this signaling. Consistent with these findings, β-arrestin-mediated ERK activation is enhanced by overexpression of GRK 5 and 6, and reciprocally diminished by GRK 2 and 3. These findings indicate distinct functional capabilities of β-arrestins bound to receptors phosphorylated by different classes of GRKs.

Original languageEnglish (US)
Pages (from-to)1442-1447
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number5
DOIs
StatePublished - Feb 1 2005
Externally publishedYes

Keywords

  • Angiotensin receptor
  • Extracellular signal-regulated kinase
  • Phosphorylation
  • Small interfering RNA

ASJC Scopus subject areas

  • General

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