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

• Published in: The Journal of biological chemistry Vol. 279; no. 23; p. 24108
• Main Authors: Jakob Lerche Hansen, Juliane Theilade, Stig HaunsÃ, Søren P. Sheikh
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 04.06.2004
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M400092200

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 (AT 1 ) 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 AT 1 receptors exist as oligomers in transfected COS-7 cells. AT 1 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 AT 1 receptor export from the endoplasmic reticulum or Golgi by using regulated secretion/aggregation technology (RPD™). Co-expression studies of wild type AT 1 and AT 1 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 Gα q activation, whereas ERK activation was preserved. These data suggest that distinctly active conformations of AT 1 oligomers can couple to each of these signaling systems and imply that oligomerization plays an active role in supporting these distinctly active conformations of AT 1 receptors.