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

J. L. Hansen,J. Theilade,S. Haunsø,S. Sheikh

Published 2004 in Journal of Biological Chemistry

ABSTRACT

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™). 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 Gαq 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.

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