Angiotensin II type 2 receptor-bradykinin B2 receptor functional heterodimerization
Angiotensin II type 2 receptor-bradykinin B2 receptor functional heterodimerization
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DOI：
10.1161/01.hyp.0000228997.88162.a8
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发表时间：
2006-08-01
期刊：
影响因子：
8.3
通讯作者：
Siragy, Helmy M.
中科院分区：
文献类型：
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作者：
Abadir, Peter M.;Periasamy, Ammasi;Siragy, Helmy M.
血管紧张素II 2型（AT（2）R）或缓激肽B-2（B2 R）受体激活可增强NO的产生。最近，我们证明了当AT（2）R和B2 R同时激活时，体内NO产生增加。然而，这种增强的机制尚不清楚。使用共聚焦荧光共振能量转移显微镜，我们报告了PC 12 W细胞膜中AT（2）R和B2 R之间的距离为50 +/- 5埃，提供了证据和受体异源二聚化作为增强NO产生的机制的定量。AT（2）R-B2 R异二聚体形成的速率在很大程度上是AT（2）R-B2 R表达程度的函数。二聚化受体之间的物理结合引发细胞内磷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κ B α和激活转录因子2的磷酸化; p38和p42/44促分裂原激活蛋白激酶和信号转导转录抑制剂3的去磷酸化;以及NO和cGMP的产生增强。控制AT（2）R-B2 R的表达，从而影响其生物活性二聚体，为治疗高血压和其他心血管和肾脏疾病提供了潜在的治疗靶点。
Angiotensin II type 2 (AT(2)R) or bradykinin B-2 (B2R) receptor activation enhances NO production. Recently, we demonstrated enhancement of NO production when AT(2)R 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 AT(2)R and B2R in PC12W cell membranes to be 50 +/- 5 angstrom, providing evidence and quantification of receptor heterodimerization as the mechanism for enhancing NO production. The rate of AT(2)R-B2R heterodimer formation is largely a function of the degree of AT(2)R-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 kappa B alpha, 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-B2R, consequently influencing their biologically active dimerization, presents a potential therapeutic target for the treatment of hypertension and other cardiovascular and renal disorders.