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(Circulation Research. 2000;86:729.)
© 2000 American Heart Association, Inc.

Molecular Medicine

The Third Cytoplasmic Loop of the Angiotensin II Type 1 Receptor Exerts Differential Effects on Extracellular Signal–Regulated Kinase (ERK1/ERK2) and Apoptosis via Ras- and Rap1-Dependent Pathways

Judith Haendeler, Mari Ishida, Laszlo Hunyady, Bradford C. Berk

From the Center for Cardiovascular Research, University of Rochester, Rochester, NY. Present address of M.I. is Department of Clinical Laboratory, Hiroshima University School of Medicine, Japan; present address of L.H. is Department of Physiology, Semmelweis University of Medicine, Budapest, Hungary.

Correspondence to Bradford C. Berk, MD, PhD, Center for Cardiovascular Research, University of Rochester, 601 Elmwood Ave, Box 679, Rochester, NY 14642. E-mail bradford_berk{at}urmc.rochester.edu

Abstract—The third cytoplasmic loop of the angiotensin (Ang) II type 1 receptor (AT₁) is important for receptor coupling to G proteins and activation of downstream events. Therefore, we determined whether specific AT₁ sequences were required for kinase activation and inhibition of apoptosis by transfecting wild-type (AT1Rwt) and mutated AT₁ into 293 cells. Ang II stimulated a 19.4-fold increase in extracellular signal–regulated kinase (ERK1/ERK2) activity in 293 cells transfected with AT1Rwt. However, in 293 cells that expressed a receptor in which amino acids 221 and 222 were deleted (AT1R[Del221/222]), Ang II–mediated ERK1/ERK2 activation was inhibited by >85%. In contrast, c-Jun NH₂-terminal protein kinase (JNK) activation was similar in AT1Rwt- and AT1R(Del221/222)-transfected cells. Activation of ERK1/ERK2 by AT1Rwt was independent of Ca²⁺, whereas the low level of ERK1/ERK2 activation by AT1R(Del221/222) was completely Ca²⁺ dependent. Activation of ERK1/ERK2 in AT1Rwt required Ras, whereas AT1R(Del221/222) required Rap1. These results demonstrate the presence of 2 different pathways for ERK1/ERK2 activation by Ang II, which differ in their requirements for Ca²⁺ and small G proteins (Ras versus Rap1). Furthermore, Ang II prevented serum deprivation–induced apoptosis in cells transfected with AT1Rwt but not AT1R(Del221/222). AKT was only phosphorylated by Ang II in AT1Rwt-transfected cells. Overexpression of constitutively active AKT significantly reduced serum deprivation–induced apoptosis in cells transfected with AT1R(Del221/222). This study shows for the first time a direct link between kinase activation and inhibition of apoptosis dependent on amino acids 221 and 222 in the third cytoplasmic loop of the AT₁.

Key Words: angiotensin II • apoptosis • AT₁ • kinases

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