Cardiovascular Pathobiology Program, Sanford Burnham Medical Research Institute at Lake Nona, Orlando, FL, USA.
Br J Pharmacol. 2013 Mar;168(5):1104-17. doi: 10.1111/j.1476-5381.2012.02192.x.
The apelin receptor (APJ) is often co-expressed with the angiotensin II type-1 receptor (AT1) and acts as an endogenous counter-regulator. Apelin antagonizes Ang II signalling, but the precise molecular mechanism has not been elucidated. Understanding this interaction may lead to new therapies for the treatment of cardiovascular disease.
The physical interaction of APJ and AT1 receptors was detected by co-immunoprecipitation and bioluminescence resonance energy transfer (BRET). Functional and pharmacological interactions were measured by G-protein-dependent signalling and recruitment of β-arrestin. Allosterism and cooperativity between APJ and AT1 were measured by radioligand binding assays.
Apelin, but not Ang II, induced APJ : AT1 heterodimerization forced AT1 into a low-affinity state, reducing Ang II binding. Likewise, apelin mediated a concentration-dependent depression in the maximal production of inositol phosphate (IP(1) ) and β-arrestin recruitment to AT1 in response to Ang II. The signal depression approached a limit, the magnitude of which was governed by the cooperativity indicative of a negative allosteric interaction. Fitting the data to an operational model of allosterism revealed that apelin-mediated heterodimerization significantly reduces Ang II signalling efficacy. These effects were not observed in the absence of apelin.
Apelin-dependent heterodimerization between APJ and AT1 causes negative allosteric regulation of AT1 function. As AT1 is significant in the pathogenesis of cardiovascular disease, these findings suggest that impaired apelin and APJ function may be a common underlying aetiology.
This article is commented on by Goupil et al., pp. 1101-1103 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12040.
阿片肽受体（APJ）常与血管紧张素 II 型 1 型受体（AT1）共同表达，并作为内源性的拮抗物。阿片肽拮抗 Ang II 信号，但确切的分子机制尚未阐明。了解这种相互作用可能会为心血管疾病的治疗带来新的疗法。
通过共免疫沉淀和生物发光共振能量转移（BRET）检测 APJ 和 AT1 受体的物理相互作用。通过 G 蛋白依赖性信号和β-arrestin 的募集来测量功能和药理学相互作用。通过放射性配体结合测定来测量 APJ 和 AT1 之间的变构和协同作用。
阿片肽而非 Ang II 诱导 APJ ： AT1 异源二聚化将 AT1 置于低亲和力状态，减少 Ang II 结合。同样，阿片肽介导了 Ang II 引起的三磷酸肌醇（IP(1)）最大产量和β-arrestin 募集到 AT1 的浓度依赖性抑制。这种信号抑制接近一个极限，其大小由协同性决定，协同性指示负变构相互作用。将数据拟合到变构作用的操作模型表明，阿片肽介导的异源二聚化显著降低了 Ang II 信号的功效。在没有阿片肽的情况下，没有观察到这些效应。
APJ 和 AT1 之间的阿片肽依赖性异源二聚化导致 AT1 功能的负变构调节。由于 AT1 在心血管疾病的发病机制中很重要，这些发现表明，阿片肽和 APJ 功能受损可能是共同的潜在病因。
本文由 Goupil 等人评论，见本期第 1101-1103 页。要查看此评论，请访问 http://dx.doi.org/10.1111/bph.12040。
