Published Online
on June 5, 2006

A more recent version of this article appeared on August 1, 2006

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Submitted on January 12, 2006
Revised on January 30, 2006

Angiotensin II Type 2 Receptor-Bradykinin B₂ Receptor Functional Heterodimerization

Peter M. Abadir; Ammasi Periasamy; Robert M. Carey; and Helmy M. Siragy^*

From the Division of Endocrinology and Metabolism, Department of Medicine and W. M. Keck Center for Cell Imaging, University of Virginia, Charlottesville.

^* To whom correspondence should be addressed. E-mail: hms7a{at}virginia.edu.

Abstract--Angiotensin II type 2 (AT₂R) or bradykinin B₂ (B₂R) receptor activation enhances NO production. Recently, we demonstrated enhancement of NO production when AT₂R and B₂R are simultaneously activated in vivo. However, the mechanism involved in this enhancement is unknown. Using confocal fluorescence resonance energy transfer microscopy, we report the distance between the AT₂R and B₂R in PC12W cell membranes to be 50±5 Å, providing evidence and quantification of receptor heterodimerization as the mechanism for enhancing NO production. The rate of AT₂R-B₂R heterodimer formation is largely a function of the degree of AT₂R-B₂R expression. The physical association between the dimerized receptors initiates changes in intracellular phosphoprotein signaling activities leading to phosphorylation of c-Jun terminal kinase, phosphotyrosine phosphatase, inhibitory protein B, and activating transcription factor 2; dephosphorylation of p38 and p42/44 mitogen-activated protein kinase and signal transducer inhibitor of transcription 3; and enhancing production of NO and cGMP. Controlling the expression of AT₂R-B₂R, consequently influencing their biologically active dimerization, presents a potential therapeutic target for the treatment of hypertension and other cardiovascular and renal disorders.

Key words: receptors, bradykinin • nitric oxide • angiotensin • bradykinin

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