In “Cannabinoid regulation of angiotensin II-induced calcium signaling in striatal neurons” we investigated the functional interactions between AT₁ and CB₁ receptors in the striatum, a brain region critical for motor control and dramaticallyaffected by Parkinson's Disease (PD).

First, using bioluminescence resonance energy transfer (BRET) assays, we demonstrated that AT₁R and CB₁R form heterodimers (AT₁CB₁Hets) in HEK-293T co-transfected cells. These findings were supported by in situ proximity ligation assays (PLA) that confirmed the natural formation of AT₁CB₁Hets in striatal neurons.

Next, we examined the AT₁CB₁Hets functionality. Through cAMP determination assays in HEK-293T co-transfected cells and striatal neurons, we discovered a "cross-antagonism" effect: blocking one receptor with its specific antagonist also prevented the agonist of the other receptor from working.

We also investigated calcium signaling, as activation of AT₁Rs leads to an increase in intracellular Ca²⁺ levels. Our results showed that this AT₁R-mediated increase in Ca²⁺ was significantly reduced by the activation of CB₁Rs with a selective cannabinoid. These results indicate the potential of cannabinoids in regulating calcium homeostasis.

Interestingly, analysis of a 6-hydroxydopamine (6-OHDA) hemilesioned rat model of PD shown a lower expression of AT₁CB₁Hets in striatal neurons of lesioned animals compared to non-lesioned controls. In fact, AT₁CB₁Hets expression change depending on the presence and effects of levodopa administration, with partial recovery in animals that developed dyskinesias. These data suggest a compensatory mechanism in response to dyskinesias involving the AT₁CB₁Hets.

In conclusion, our findings suggests that cannabinoids may hold promise in mitigating calcium dyshomeostasis associated with PD and levodopa-induced dyskinesias. Future studies should examine AT₁CB₁Hets in PD pathophysiology and determine their potential as a novel target for pharmacological research.