Rivas‐Santisteban, RafaelRodríguez Pérez, Ana I.Muñoz, AnaReyes Resina, IreneLabandeira García, José L.Navarro Brugal, GemmaFranco Fernández, Rafael2021-03-182021-03-182020-02-011015-8987https://hdl.handle.net/2445/175330Background/Aims : The renin-angiotensin system (RAS) is altered in Parkinson's disease (PD), a disease due to substantia nigra neurodegeneration and whose dopamine-replacement therapy, using the precursor levodopa, leads to dyskinesias as the main side effect. Angiotensin AT 1 and AT 2 receptors, mainly known for their role in regulating water homeostasis and blood pressure and able to form heterodimers (AT 1/2 Hets), are present in the central nervous system. We assessed the functionality and expression of AT 1/2 Hets in Parkinson Disease (PD). Methods: Immunocytochemistry was used to analyze the colocalization between angiotensin receptors, bioluminescence resonance energy transfer was used to detect AT 1/2 Hets. Calcium and cAMP determination, MAPK activation and label-free assays were performed to characterize signaling. Proximity ligation assays was used to quantify receptor expression in microglial cells and brain striatal slices. Results: We confirmed that AT 1 and AT 2 receptors form AT 1/2 Hets that are expressed in cells of the central nervous system. AT 1/2 Hets are novel functional units with particular signaling properties. Importantly, the coactivation of the two receptors in the heteromer reduces the signaling output of angiotensin. Remarkably, AT 1/2 Hets that are expressed in both striatal neurons and microglia show a cross-potentiation, i.e. candesartan, the antagonist of AT 1 increases the effect of AT 2 receptor agonists. In addition, the level of expression in the unilateral 6-OH-dopamine lesion rat PD model increases upon disease progression and is maximal in dyskinetic animals. Conclusion: The results indicate that boosting the action of neuroprotective AT 2 receptors using an AT 1 receptor antagonist constitutes a promising therapeutic strategy in PD.application/pdfengcc-by-nc (c) Karger, 2020http://creativecommons.org/licenses/by-nc/3.0/esReceptors cel·lularsMalaltia de ParkinsonMalalties neurodegenerativesCell receptorsParkinson's diseaseNeurodegenerative Diseasesinfo:eu-repo/semantics/article6999792021-03-18info:eu-repo/semantics/openAccess