Hansen Jakob L, Hansen Jonas T, Speerschneider Tobias, Lyngsø Christina, Erikstrup Niels, Burstein Ethan S, Weiner David M, Walther Thomas, Makita Noriko, Iiri Taroh, Merten Nicole, Kostenis Evi, Sheikh Søren P
Laboratory for Molecular Cardiology, The Danish National Research Foundation Centre for Cardiac Arrhythmia, The Heart Centre, Copenhagen University Hospital, Copenhagen, Denmark.
J Biol Chem. 2009 Jan 16;284(3):1831-9. doi: 10.1074/jbc.M804607200. Epub 2008 Nov 18.
It has been suggested previously ( AbdAlla, S., Lother, H., and Quitterer, U. (2000) Nature 407, 94-98 ) that the angiotensin II type 1 receptor (AT1R) and the bradykinin B2 receptor (B2R) form constitutive heterodimers. Furthermore they demonstrate that AT1R signaling significantly increases in the presence of the B2R. These findings suggest that heterodimerization and potentiation of AT1R signaling is a universal phenomenon that occurs as a natural consequence of simultaneous expression of the two receptors. Hence this potential interaction is of great pharmacological and biological interest that adds an additional layer of complexity to the understanding of the cross-talk between the renin-angiotensin and kallikrein-kinin systems. Given the remarkable significance of this finding, scientists from four independent research groups have set out to reproduce and further examine the potential AT1R/B2R interaction. We have investigated functional potentiation by the B2R of AT1R signaling in three different cell lines using multiple assays including phosphoinositide hydrolysis, ERK activation, beta-arrestin recruitment, and receptor selection and amplification technology, and we have examined dimerization using bioluminescence resonance energy transfer and regulated secretion/aggregation technology. However, although both the AT1Rs and B2Rs were functional in our systems and the systems were fine tuned to detect small changes in receptor function, we failed to detect any functional modulation by or physical interaction between the two receptor proteins. In contrast to the previous observations, our data collectively suggest that AT1R/B2R heterodimerization does not occur as a natural consequence of their simultaneous expression in the same cell nor does the B2R influence the AT1R signaling.
先前有人提出（AbdAlla, S., Lother, H., and Quitterer, U. (2000) 《自然》407, 94 - 98），血管紧张素II 1型受体（AT1R）和缓激肽B2受体（B2R）形成组成型异二聚体。此外，他们证明在B2R存在的情况下，AT1R信号显著增强。这些发现表明，AT1R信号的异二聚化和增强是一种普遍现象，是两种受体同时表达的自然结果。因此，这种潜在的相互作用具有极大的药理学和生物学意义，为理解肾素 - 血管紧张素系统和激肽释放酶 - 激肽系统之间的相互作用增添了额外的复杂性。鉴于这一发现的显著意义，四个独立研究小组的科学家已着手重现并进一步研究潜在的AT1R/B2R相互作用。我们使用多种检测方法，包括磷酸肌醇水解、ERK激活、β - 抑制蛋白募集以及受体选择和扩增技术，在三种不同的细胞系中研究了B2R对AT1R信号的功能增强作用，并且我们使用生物发光共振能量转移和调节分泌/聚集技术检测了二聚化。然而，尽管在我们的系统中AT1R和B2R均有功能，并且该系统经过精细调整以检测受体功能的微小变化，但我们未能检测到两种受体蛋白之间的任何功能调节或物理相互作用。与先前的观察结果相反，我们的数据共同表明，AT1R/B2R异二聚化并非它们在同一细胞中同时表达的自然结果，并且B2R也不影响AT1R信号。
