βb-arrestin-biased agonism of the angiotensin receptor induced by mechanical stress

Kriti Rakesh, Byung Su Yoo, Il-man Kim, Natasha Salazar, Ki Seok Kim, Howard A. Rockman

Research output: Contribution to journalArticle

120 Citations (Scopus)

Abstract

β-Arrestins, which were originally characterized as terminators of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) signaling, also act as important signal transducers. An emerging concept in GPCR signaling is β-arrestin-biased agonism, in which specific ligand-activated GPCR conformational states selectively signal through β-arrestins, rather than through G proteins. Here, we show that mechanical stretch induced β-arrestin-biased signaling downstream of angiotensin II type I receptors (AT1Rs) in the absence of ligand or G protein activation. Mechanical stretch triggered an AT1Rmediated conformational change in β-arrestin similar to that induced by a β-arrestin-biased ligand to selectively stimulate receptor signaling in the absence of detectable G protein activation. Hearts from mice lacking β-arrestin or AT1Rs failed to induce responses to mechanical stretch, as shown by blunted extracellular signal-regulated kinase and Akt activation, impaired transactivation of the epidermal growth factor receptor, and enhancedmyocyte apoptosis. These data show that the heart responds to acute increases in mechanical stress by activating β-arrestin-mediated cell survival signals.

Original languageEnglish (US)
JournalScience Signaling
Volume3
Issue number125
DOIs
StatePublished - Jun 8 2010

Fingerprint

Arrestin
Mechanical Stress
Angiotensin Receptors
G-Protein-Coupled Receptors
Arrestins
GTP-Binding Proteins
Chemical activation
Ligands
Angiotensin I
Guanine Nucleotides
Extracellular Signal-Regulated MAP Kinases
Transducers
Epidermal Growth Factor Receptor
Angiotensin II
Transcriptional Activation
Cell Survival
Carrier Proteins
Cells
Apoptosis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Rakesh, K., Yoo, B. S., Kim, I., Salazar, N., Kim, K. S., & Rockman, H. A. (2010). βb-arrestin-biased agonism of the angiotensin receptor induced by mechanical stress. Science Signaling, 3(125). https://doi.org/10.1126/scisignal.2000769

βb-arrestin-biased agonism of the angiotensin receptor induced by mechanical stress. / Rakesh, Kriti; Yoo, Byung Su; Kim, Il-man; Salazar, Natasha; Kim, Ki Seok; Rockman, Howard A.

In: Science Signaling, Vol. 3, No. 125, 08.06.2010.

Research output: Contribution to journalArticle

Rakesh, Kriti ; Yoo, Byung Su ; Kim, Il-man ; Salazar, Natasha ; Kim, Ki Seok ; Rockman, Howard A. / βb-arrestin-biased agonism of the angiotensin receptor induced by mechanical stress. In: Science Signaling. 2010 ; Vol. 3, No. 125.
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