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(Hypertension. 2006;48:316.)
© 2006 American Heart Association, Inc.

Original Articles

Angiotensin II Type 2 Receptor–Bradykinin B₂ Receptor Functional Heterodimerization

Peter M. Abadir; Ammasi Periasamy; Robert M. Carey; 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.

Correspondence to Helmy M. Siragy, PO Box 801409, University of Virginia Health System, Charlottesville, VA 22908-1409. E-mail hms7a{at}virginia.edu

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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