Abadir Peter M, Periasamy Ammasi, Carey Robert M, Siragy Helmy M
Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia, Charlottesville, VA, USA.
Hypertension. 2006 Aug;48(2):316-22. doi: 10.1161/01.HYP.0000228997.88162.a8. Epub 2006 Jun 5.
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.
血管紧张素 II 2 型（AT2R）或缓激肽 B2（B2R）受体激活可增强一氧化氮（NO）的生成。最近，我们证明了在体内同时激活 AT2R 和 B2R 时，NO 的生成会增强。然而，这种增强所涉及的机制尚不清楚。利用共聚焦荧光共振能量转移显微镜，我们报告了 PC12W 细胞膜中 AT2R 和 B2R 之间的距离为 50±5 埃，为受体异二聚化作为增强 NO 生成的机制提供了证据和量化数据。AT2R - B2R 异二聚体形成的速率在很大程度上取决于 AT2R - B2R 的表达程度。二聚化受体之间的物理缔合引发细胞内磷酸化蛋白信号传导活性的变化，导致 c - Jun 末端激酶、磷酸酪氨酸磷酸酶、抑制蛋白κBα和激活转录因子 2 的磷酸化；p38 和 p42/44 丝裂原活化蛋白激酶以及转录信号转导抑制因子 3 的去磷酸化；以及增强 NO 和环磷酸鸟苷（cGMP）的生成。控制 AT2R - B2R 的表达，进而影响它们的生物活性二聚化，为治疗高血压及其他心血管和肾脏疾病提供了一个潜在的治疗靶点。
