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

TY - JOUR

T1 - 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

AU - Aplin, Mark

AU - Christensen, Gitte Lund

AU - Schneider, Mikael

AU - Heydorn, Arne

AU - Gammeltoft, Steen

AU - Kjølbye, Anne Louise

AU - Sheikh, Søren P

AU - Hansen, Jakob Lerche

PY - 2007/5

Y1 - 2007/5

N2 - 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.

AB - 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.

KW - 1-Sarcosine-8-Isoleucine Angiotensin II

KW - Angiotensin II

KW - Animals

KW - Animals, Newborn

KW - Arrestins

KW - Cell Nucleus

KW - Cells, Cultured

KW - Coronary Circulation

KW - Cytosol

KW - GTP-Binding Proteins

KW - Heart Rate

KW - Heart Ventricles

KW - Male

KW - Mitogen-Activated Protein Kinase 1

KW - Mitogen-Activated Protein Kinase 3

KW - Muscle Contraction

KW - Myocardium

KW - Myocytes, Cardiac

KW - Perfusion

KW - Rats

KW - Rats, Sprague-Dawley

KW - Rats, Wistar

KW - Receptor, Angiotensin, Type 1

U2 - 10.1111/j.1742-7843.2007.00063.x

DO - 10.1111/j.1742-7843.2007.00063.x

M3 - Journal article

C2 - 17448113

SN - 1742-7835

VL - 100

SP - 289

EP - 295

JO - Basic and Clinical Pharmacology and Toxicology

JF - Basic and Clinical Pharmacology and Toxicology

IS - 5

ER -