The angiotensin type 1 receptor activates extracellular signal-regulated kinases 1 and 2 by G protein-dependent and -independent pathways in cardiac myocytes and langendorff-perfused hearts
Research output: Contribution to journal › Journal article › Research › peer-review
The angiotensin II (AngII) type 1 receptor (AT(1)R) has been shown to activate extracellular signal-regulated kinases 1 and 2 (ERK1/2) through G proteins or G protein-independently through beta-arrestin2 in cellular expression systems. As activation mechanisms may greatly influence the biological effects of ERK1/2 activity, differential activation of the AT(1)R in its native cellular context could have important biological and pharmacological implications. To examine if AT(1)R activates ERK1/2 by G protein-independent mechanisms in the heart, we used the [Sar(1), Ile(4), Ile(8)]-AngII ([SII] AngII) analogue in native preparations of cardiac myocytes and beating hearts. We found that [SII] AngII does not activate G(q)-coupling, yet stimulates the beta-arrestin2-dependent ERK1/2. The G(q)-activated pool of ERK1/2 rapidly translocates to the nucleus, while the beta-arrestin2-scaffolded pool remains in the cytosol. Similar biased agonism was achieved in Langendorff-perfused hearts, where both agonists elicit ERK1/2 phosphorylation, but [SII] AngII induces neither inotropic nor chronotropic effects.
Original language | English |
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Journal | Basic & Clinical Pharmacology & Toxicology |
Volume | 100 |
Issue number | 5 |
Pages (from-to) | 289-95 |
Number of pages | 7 |
ISSN | 1742-7835 |
DOIs | |
Publication status | Published - May 2007 |
- 1-Sarcosine-8-Isoleucine Angiotensin II, Angiotensin II, Animals, Animals, Newborn, Arrestins, Cell Nucleus, Cells, Cultured, Coronary Circulation, Cytosol, GTP-Binding Proteins, Heart Rate, Heart Ventricles, Male, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Muscle Contraction, Myocardium, Myocytes, Cardiac, Perfusion, Rats, Rats, Sprague-Dawley, Rats, Wistar, Receptor, Angiotensin, Type 1
Research areas
ID: 34167892