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.
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.
Aplin
Mark
M
Laboratory for Molecular Cardiology, 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; D019390:Arrestins / Q000378:metabolism; D002467:Cell Nucleus / Q000201:enzymology; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis*; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis*; D009119:Muscle Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D000071557:beta-Arrestins
D019390:Arrestins; D044140:Receptor, Angiotensin, Type 1; D000071557:beta-Arrestins; D000804:Angiotensin II; D015059:1-Sarcosine-8-Isoleucine Angiotensin II; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019204:GTP-Binding Proteins