The renin–angiotensin system (RAS) not only plays an important role in controlling blood pressure but also participates in almost every process to maintain homeostasis in mammals. Interest has recently increased because SARS viruses use one RAS component (ACE2) as a target-cell receptor. The occurrence of RAS in the basal ganglia suggests that the system may be targeted to improve the therapy of neurodegenerative diseases. RAS-related data led to the hypothesis that RAS receptors may interact with each other. The aim of this paper was to find heteromers formed by Mas and angiotensin receptors and to address their functionality in neurons and microglia. Novel interactions were discovered by using resonance energy transfer techniques. The functionality of individual and interacting receptors was assayed by measuring levels of the second messengers cAMP and Ca²⁺ in transfected human embryonic kidney cells (HEK-293T) and primary cultures of striatal cells. Receptor complex expression was assayed by in situ proximity ligation assay. Functionality and expression were assayed in parallel in primary cultures of microglia treated or not with lipopolysaccharide and interferon-γ (IFN-γ). The proximity ligation assay was used to assess heteromer expression in parkinsonian and dyskinetic conditions. Complexes formed by Mas and the angiotensin AT₁ or AT₂ receptors were identified in both a heterologous expression system and in neural primary cultures. In the heterologous system, we showed that the three receptors—MasR, AT₁R, and AT₂R—can interact to form heterotrimers. The expression of receptor dimers (AT₁R-MasR or AT₂R-MasR) was higher in microglia than in neurons and was differentially affected upon microglial activation with lipopolysaccharide and IFN-γ. In all cases, agonist-induced signaling was reduced upon coactivation, and in some cases just by coexpression. Also, the blockade of signaling of two receptors in a complex by the action of a given (selective) receptor antagonist (cross-antagonism) was often observed. Differential expression of the complexes was observed in the striatum under parkinsonian conditions and especially in animals rendered dyskinetic by levodopa treatment. The negative modulation of calcium mobilization (mediated by AT₁R activation), the multiplicity of possibilities on RAS affecting the MAPK pathway, and the disbalanced expression of heteromers in dyskinesia yield new insight into the operation of the RAS system, how it becomes unbalanced, and how a disbalanced RAS can be rebalanced. Furthermore, RAS components in activated microglia warrant attention in drug-development approaches to address neurodegeneration.

肾素-血管紧张素系统（RAS）不仅在控制血压方面发挥着重要作用，而且还参与哺乳动物维持体内平衡的几乎每个过程。最近，人们对 SARS 病毒的兴趣有所增加，因为 SARS 病毒使用一种 RAS 成分 (ACE2) 作为靶细胞受体。基底神经节中 RAS 的出现表明该系统可能有针对性地改善神经退行性疾病的治疗。 RAS 相关数据引发了 RAS 受体可能相互作用的假设。本文的目的是寻找 Mas 和血管紧张素受体形成的异聚体，并研究它们在神经元和小胶质细胞中的功能。通过使用共振能量转移技术发现了新的相互作用。通过测量转染的人胚胎肾细胞 (HEK-293T) 和纹状体细胞原代培养物中第二信使 cAMP 和 Ca ²⁺的水平来分析单个受体和相互作用受体的功能。通过原位邻近连接测定法测定受体复合物表达。在用脂多糖和干扰素-γ (IFN-γ) 处理或未处理的小胶质细胞的原代培养物中平行测定功能和表达。邻近连接测定用于评估帕金森病和运动障碍条件下的异聚体表达。 Mas 与血管紧张素 AT ₁或 AT ₂受体形成的复合物在异源表达系统和神经原代培养物中均得到鉴定。在异源系统中，我们发现三种受体——MasR、AT ₁ R 和 AT ₂ R——可以相互作用形成异源三聚体。 小胶质细胞中受体二聚体（AT ₁ R-MasR 或 AT ₂ R-MasR）的表达高于神经元中的表达，并且脂多糖和 IFN-γ 对小胶质细胞激活的影响存在差异。在所有情况下，激动剂诱导的信号传导在共激活时都会减少，在某些情况下仅通过共表达而减少。此外，经常观察到通过给定（选择性）受体拮抗剂（交叉拮抗作用）的作用来阻断复合物中两个受体的信号传导。在帕金森病条件下，特别是在左旋多巴治疗导致运动障碍的动物中，在纹状体中观察到复合物的差异表达。钙动员的负调节（由 AT ₁ R 激活介导）、RAS 影响 MAPK 途径的多种可能性以及运动障碍中异聚体的不平衡表达，使我们对 RAS 系统的运作及其如何变得不平衡产生了新的见解。以及如何重新平衡不平衡的 RAS。此外，激活小胶质细胞中的 RAS 成分值得在解决神经退行性疾病的药物开发方法中引起关注。