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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
Author(s) -
Aplin Mark,
Christensen Gitte Lund,
Schneider Mikael,
Heydorn Arne,
Gammeltoft Steen,
Kjølbye Anne Louise,
Sheikh Søren P.,
Hansen Jakob Lerche
Publication year - 2007
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2007.00063.x
Subject(s) - angiotensin ii , chronotropic , extracellular , chemistry , kinase , cytosol , microbiology and biotechnology , signal transduction , receptor , context (archaeology) , myocyte , biology , endocrinology , biochemistry , paleontology , heart rate , blood pressure , enzyme
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 β‐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 β‐arrestin2‐dependent ERK1/2. The G q ‐activated pool of ERK1/2 rapidly translocates to the nucleus, while the β‐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.