Angiotensin AT(1) and AT(2) receptor heteromer expression in the hemilesioned rat model of Parkinson’s disease that increases with levodopa-induced dyskinesia

BACKGROUND/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 in homologous and heterologous systems. Proximity ligation assays were used to quantify receptor expression in mouse primary cultures and in rat striatal sections. 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 make possible that candesartan, the antagonist of AT(1), increases the effect of AT(2) 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. 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.