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Novel Interactions between Mas and Angiotensin Receptors and Their Functionality Modulatory Role for the Brain RAS †

Department Biochemistry and Molecular Biomedicine, School of Biology, University of Barcelona, 08028 Barcelona, Spain
Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIberNed), Instituto de Salud Carlos III, Valderrebollo 5, 28031 Madrid, Spain
Laboratory of Cellular and Molecular Neurobiology of Parkinson’s Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), Department of Morphological Sciences, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
Department of Biochemistry and Physiology, School of Pharmacy and Food Science, University of Barcelona, 08028 Barcelona, Spain
Author to whom correspondence should be addressed.
Presented at the 2nd International Electronic Conference on Brain Sciences, 15–30 July 2021. Available online:
Med. Sci. Forum 2022, 8(1), 6;
Published: 14 July 2021
(This article belongs to the Proceedings of The 2nd International Electronic Conference on Brain Sciences)


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. The occurrence of RAS in the basal ganglia suggests that the system may be targeted to improve the therapy of neurodegenerative diseases. We found heteromers formed by Mas and angiotensin receptors, and addressed their functionality in neurons and microglia. Novel interactions formed by MAS/AT1R and MAS/AT2R were discovered by using resonance energy transfer techniques. In the heterologous system, we showed that the three receptors—MasR, AT1R, and AT2R—can interact to form heterotrimers (Figure S1). 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) (Figure S2) and primary cultures of striatal cells. Expression (Figure S3) and functionality (Figure S4) were assayed in parallel in primary cultures of microglia treated or not treated with lipopolysaccharide and interferon-γ (IFN-γ) to simulate neuroinflammation conditions. The proximity ligation assay (PLA) was used to assess heteromer expression in parkinsonian and dyskinetic conditions (Figure S4). In all cases, agonist-induced signaling was reduced upon coactivation, and in some cases just by coexpression. In addition, the blockade of signaling of two receptors in a complex by the action of a given (selective) receptor antagonist (cross-antagonism) was often observed. 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 insights into the operation of the RAS system, how it becomes unbalanced, and how a disbalanced RAS system can be rebalanced. Furthermore, RAS components in activated microglia warrant attention in drug development approaches to address neurodegeneration.

Supplementary Materials

The following are available online at Figure S1: Interaction between angiotensin (AT1 and AT2) and Mas receptors in a heterologous expression system, Figure S2: Functionality of AT1Mas and AT2Mas Hets in a heterologous expression system; Figure S3: Expression of AT1Mas and AT2Mas Hets in the striatum of parkinsonian and dyskinetic rats; Figure S4: Functionality of AT1Mas and AT2Mas Hets in activated microglia.

Author Contributions

Conceptualization (J.L.L.-G.; G.N.; R.F.), methodology and investigation (R.R.-S.), supervision (G.N.; R.F.), data curation (A.M.; A.I.R.-P.; J.L.; N.D.-M.), funding acquisition (R.F.). All authors have read and agreed to the published version of the manuscript.


This work was partially supported by grants from the Spanish Ministry of Science and Innovation (MICINN) and/or Science, Innovation, and Universities; they may include EU FEDER funds (BFU2015-64405-R, SAF2016-77830-R, AARFD-17-503612, SAF2017-84117-R, RTI2018-094204-B-I00, and RTI2018-098830-B-I00). The laboratory of the University of Barcelona is considered of excellence by the Regional Catalonian Government (grup consolidat #2017SGR 1497), which dos not provide any specific funding for personnel, equipment, and reagents or for payment of services.

Data Availability Statement

Data available on request from the authors.

Conflicts of Interest

The authors declare no conflict of interest.
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MDPI and ACS Style

Rivas-Santisteban, R.; Lillo, J.; Muñoz, A.; Rodríguez-Pérez, A.I.; Labandeira-García, J.L.; Domínguez-Madrid, N.; Navarro, G.; Franco, R. Novel Interactions between Mas and Angiotensin Receptors and Their Functionality Modulatory Role for the Brain RAS. Med. Sci. Forum 2022, 8, 6.

AMA Style

Rivas-Santisteban R, Lillo J, Muñoz A, Rodríguez-Pérez AI, Labandeira-García JL, Domínguez-Madrid N, Navarro G, Franco R. Novel Interactions between Mas and Angiotensin Receptors and Their Functionality Modulatory Role for the Brain RAS. Medical Sciences Forum. 2022; 8(1):6.

Chicago/Turabian Style

Rivas-Santisteban, Rafael, Jaume Lillo, Ana Muñoz, Ana I. Rodríguez-Pérez, José Luís Labandeira-García, Nerea Domínguez-Madrid, Gemma Navarro, and Rafael Franco. 2022. "Novel Interactions between Mas and Angiotensin Receptors and Their Functionality Modulatory Role for the Brain RAS" Medical Sciences Forum 8, no. 1: 6.

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