Differential extracellular signal-regulated kinases 1 and 2 activation by the angiotensin type 1 receptor supports distinct phenotypes of cardiac myocytes.
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 beta-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 beta-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 beta-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 beta-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.
Aplin
Mark
M
Laboratory for Molecular Cardiology, The Danish National Research Foundation Centre for Cardiac Arrhythmia, and The Heart Centre, Copenhagen University Hospital, Copenhagen, Denmark.
Christensen
Gitte Lund
GL
Schneider
Mikael
M
Heydorn
Arne
A
Gammeltoft
Steen
S
Kjølbye
Anne Louise
AL
Sheikh
Søren P
SP
Hansen
Jakob Lerche
JL
D015059:1-Sarcosine-8-Isoleucine Angiotensin II / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis*; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D015059:1-Sarcosine-8-Isoleucine Angiotensin II; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3