Abstract
Background/aimsThe 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 AT1 and AT2 receptors, mainly known for their role in regulating water homeostasis and blood pressure and able to form heterodimers (AT1/2Hets), are present in the central nervous system. We assessed the functionality and expression of AT1/2Hets in Parkinson disease (PD).MethodsImmunocytochemistry was used to analyze the colocalization between angiotensin receptors; bioluminescence resonance energy transfer was used to detect AT1/2Hets. Calcium and cAMP determination, MAPK activation, and label-free assays were performed to characterize signaling in homologous and heterologous systems. Proximity ligation assays were used to quantify receptor expression in mouse primary cultures and in rat striatal sections.ResultsWe confirmed that AT1 and AT2 receptors form AT1/2Hets that are expressed in cells of the central nervous system. AT1/2Hets 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, AT1/2Hets that are expressed in both striatal neurons and microglia make possible that candesartan, the antagonist of AT1, increases the effect of AT2 receptor agonists. In addition, the level of striatal expression increased in the unilateral 6-OH-dopamine lesioned rat PD model and was markedly higher in parkinsonian-like animals that did not become dyskinetic upon levodopa chronic administration if compared with expression in those that became dyskinetic.ConclusionThe results indicate that boosting the action of neuroprotective AT2 receptors using an AT1 receptor antagonist constitutes a promising therapeutic strategy in PD.
Highlights
The renin angiotensin system (RAS) is composed of enzymes that produce angiotensin (Ang) peptides and of cell surface receptors that convey cytocrin signals to achieve specific cell responses
We analyzed the colocalization of angiotensin receptors at the plasma membrane by using HEK-293T cells coexpressing AT1R and AT2R fused to, respectively, the yellow fluorescent protein (YFP) and Renilla luciferase (Rluc)
To know whether a direct interaction between AT1 and AT2 receptors is possible, bioluminescence resonance energy transfer (BRET) assays were performed in HEK-293T cells expressing a constant amount of a fusion protein consisting of AT2R and Renilla Luciferase (AT2R-Rluc) and increasing amounts of AT1R fused to YFP (AT1R-YFP)
Summary
The renin angiotensin system (RAS) is composed of enzymes that produce angiotensin (Ang) peptides and of cell surface receptors that convey cytocrin signals to achieve specific cell responses. Ang is an important regulator of motor control, and AT1R and AT2R have been suggested as targets to combat Parkinson’s disease (PD) and related conditions such as levodopa (L-DOPA)-induced dyskinesias [38, 45]. A local RAS has been reported in the SN [20, 61], in which overactivity of AT1R correlates with aging-related alterations, neuronal death [22, 31], and neuroinflammation (Labandeira-Garcia et al, [29, 30, 52]). The search for pharmacological tools targeting G-protein-coupled receptors to convert M1 into M2 phenotype is an active field of research. The role of AT2R and the interplay between the two receptors in the abovementioned changes due to Ang action in the aged or in the pathological brain is still unclear
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