Stable interaction between β-arrestin 2 and angiotensin type 1A receptor is required for β-arrestin 2-mediated activation of extracellular signal-regulated kinases 1 and 2

Huijun Wei, Seungkirl Ahn, William G. Barnes, Robert J. Lefkowitz

Research output: Contribution to journalArticlepeer-review

Abstract

Binding of β-arrestins to seven-membrane-spanning receptors (7MSRs) not only leads to receptor desensitization and endocytosis but also elicits additional signaling processes. We recently proposed that stimulation of the angiotensin type 1A (AT1A) receptor results in independent β-arrestin 2- and G protein-mediated extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation. Here we utilize two AT1A mutant receptors to study these independent pathways, one truncated at residue 324, thus removing all potential carboxyl-terminal phosphorylation sites, and the other bearing four mutations in the serine/threonine-rich clusters in the carboxyl terminus. As assessed by confocal microscopy, the two mutant receptors interacted with β-arrestin 2-green fluorescent protein with much lower affinity than did the wild-type receptor. In addition, the mutant receptors more robustly stimulated G protein-mediated inositol phosphate production. Approximately one-half of the wild-type AT1A receptor-stimulated ERK1/2 activation was via a β-arrestin 2-dependent pathway (suppressed by β-arrestin 2 small interfering RNA), whereas the rest was mediated by a G protein-dependent pathway (suppressed by protein kinase C inhibitor). ERK1/2 activation by the mutant receptors was insensitive to β-arrestin 2 small interfering RNA but was reduced more than 80% by a protein kinase C inhibitor. The biochemical consequences of ERK activation by the G protein and β-arrestin 2-dependent pathways were also distinct. G-protein-mediated ERK activation enhanced the transcription of early growth response 1, whereas β-arrestin 2-dependent ERK activation did not. In addition, stimulation of the truncated AT1A mutant receptor caused significantly greater early growth response 1 transcription than did the wild-type receptor. These findings demonstrate how the ability of receptors to interact with β-arrestins determines both the mechanism of ERK activation as well as the physiological consequences of this activation.

Original languageEnglish (US)
Pages (from-to)48255-48261
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number46
DOIs
StatePublished - Nov 12 2004
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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