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J. Biol. Chem., Vol. 279, Issue 23, 24108-24115, June 4, 2004

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Oligomerization of Wild Type and Nonfunctional Mutant Angiotensin II Type I Receptors Inhibits G_q Protein Signaling but Not ERK Activation^*

Jakob Lerche Hansen, Juliane Theilade, Stig Haunsø, and Søren P. Sheikh

From the Laboratory of Molecular Cardiology, the Heart Centre and Copenhagen Heart Arrhythmia Research Centre, Copenhagen University Hospital Section 9312 and the Faculty of Health, University of Copenhagen, 20 Juliane Mariesvej, Copenhagen DK-2100, Denmark

The 7-transmembrane or G protein-coupled receptors relay signals from hormones and sensory stimuli to multiple signaling systems at the intracellular face of the plasma membrane including heterotrimeric G proteins, ERK1/2, and arrestins. It is an emerging concept that 7-transmembrane receptors form oligomers; however, it is not well understood which roles oligomerization plays in receptor activation of different signaling systems. To begin to address this question, we used the angiotensin II type 1 (AT₁) receptor, a key regulator of blood pressure and fluid homeostasis that in specific context has been described to activate ERKs without activating G proteins. By using bioluminescence resonance energy transfer, we demonstrate that AT₁ receptors exist as oligomers in transfected COS-7 cells. AT₁ oligomerization was both constitutive and receptor-specific as neither agonist, antagonist, nor co-expression with three other receptors affected the bioluminescence resonance energy transfer 2 signal. Furthermore, the oligomerization occurs early in biosynthesis before surface expression, because we could control AT₁ receptor export from the endoplasmic reticulum or Golgi by using regulated secretion/aggregation technology (RPD^TM). Co-expression studies of wild type AT₁ and AT₁ receptor mutants, defective in either ligand binding or G protein and ERK activation, yielded an interesting result. The mutant receptors specifically exerted a dominant negative effect on G_q activation, whereas ERK activation was preserved. These data suggest that distinctly active conformations of AT₁ oligomers can couple to each of these signaling systems and imply that oligomerization plays an active role in supporting these distinctly active conformations of AT₁ receptors.

Received for publication, January 6, 2004 , and in revised form, March 31, 2004.

^* This work was funded by the Danish Heart Foundation, The John Meyer Foundation, The Danish Medical Research Council, The A. P. Møller Foundation for the Advancement of Medical Science, The Foundation of Knud Højgaard, The Danish Medical Research Council, and The Villadsen Family Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 45-35456730; Fax: 45-35456500; E-mail: sheikh{at}molheart.dk.

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