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Differential Extracellular Signal‐Regulated Kinases 1 and 2 Activation by the Angiotensin Type 1 Receptor Supports Distinct Phenotypes of Cardiac Myocytes
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.1742-7843.2007.00064.x
Subject(s) - microbiology and biotechnology , signal transduction , angiotensin ii , kinase , gq alpha subunit , myocyte , biology , cardiac myocyte , transmembrane protein , receptor , g protein coupled receptor , biochemistry
The angiotensin II (AngII) type 1 receptor (AT 1 R) is a seven‐transmembrane receptor well established to activate extracellular signal‐regulated kinases 1 and 2 (ERK1/2) by discrete G protein‐dependent and β‐arrestin2‐dependent pathways. The biological importance of this, however, remains obscure. Application of the modified analogue [Sar 1 , Ile 4 , Ile 8 ]‐AngII ([SII] AngII) allowed us to dissect the two pathways of ERK1/2 activation in native cardiac myocytes. Although cytosol‐retained, the β‐arrestin2‐bound pool of ERK1/2 represents an active signalling component that phosphorylates p90 Ribosomal S6 Kinase, a ubiquitous and versatile mediator of ERK1/2 signal transduction. Moreover, the β‐arrestin2‐dependent ERK1/2 signal supports intact proliferation of cardiac myocytes. In contrast to G q ‐activated ERK1/2, and in keeping with its failure to translocate to the nucleus, the β‐arrestin2‐scaffolded pool of ERK1/2 does not phosphorylate the transcription factor Elk‐1, induces no increased transcription of the immediate‐early gene c‐Fos, and does not entail myocyte hypertrophy. These results clearly demonstrate the biological significance of differential signalling by the AT 1 R. The opportunity to separate desirable cardiac myocyte division from detrimental hypertrophy holds promise that novel pharmacological approaches will allow targeting of pathway‐specific actions.