Angiotensin II type 2 receptor-bradykinin B2 receptor functional heterodimerization.
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 A, 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 kappaBalpha, 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.
Abadir
Peter M
PM
Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia, Charlottesville, VA, USA.
Periasamy
Ammasi
A
Carey
Robert M
RM
Siragy
Helmy M
HM
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism* / Q000648:ultrastructure; D006152:Cyclic GMP / Q000378:metabolism; D019281:Dimerization; D031541:Fluorescence Resonance Energy Transfer; D007091:Image Processing, Computer-Assisted; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D018613:Microscopy, Confocal; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D016716:PC12 Cells; D010673:Pheochromocytoma / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D051381:Rats; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000378:metabolism*; D015398:Signal Transduction
D051698:Activating Transcription Factor 2; D010750:Phosphoproteins; D044139:Receptor, Angiotensin, Type 2; D043782:Receptor, Bradykinin B2; D009569:Nitric Oxide; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases; D006152:Cyclic GMP