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 language | English |
|---|---|
| Pages (from-to) | ra46 |
| Journal | Science Signaling |
| Volume | 3 |
| Issue number | 125 |
| DOIs | |
| Publication status | Published - 2010 Jun 8 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Molecular Biology
- Cell Biology
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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, p. ra46.Research output: Contribution to journal › Article
TY - JOUR
T1 - βb-arrestin-biased agonism of the angiotensin receptor induced by mechanical stress
AU - Rakesh, Kriti
AU - Yoo, Byung Su
AU - Kim, Il Man
AU - Salazar, Natasha
AU - Kim, Ki Seok
AU - Rockman, Howard A.
PY - 2010/6/8
Y1 - 2010/6/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77953819826&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77953819826&partnerID=8YFLogxK
U2 - 10.1126/scisignal.2000769
DO - 10.1126/scisignal.2000769
M3 - Article
C2 - 20530803
AN - SCOPUS:77953819826
VL - 3
SP - ra46
JO - Science Signaling
JF - Science Signaling
SN - 1945-0877
IS - 125
ER -