Angiotensin II Type 2 Receptor–Bradykinin B 2 Receptor Functional Heterodimerization

Angiotensin II type 2 (AT 2 R) or bradykinin B 2 (B 2 R) receptor activation enhances NO production. Recently, we demonstrated enhancement of NO production when AT 2 R and B 2 R 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 AT 2 R and B 2 R 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 AT 2 R–B 2 R heterodimer formation is largely a function of the degree of AT 2 R–B 2 R 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 κBα, 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 AT 2 R–B 2 R, consequently influencing their biologically active dimerization, presents a potential therapeutic target for the treatment of hypertension and other cardiovascular and renal disorders.