Cannabinoid regulation of angiotensin II-induced calcium signaling in striatal neurons

Calcium ion (Ca²⁺) homeostasis is crucial for neuron function and neurotransmission. This study focused on the actions mediated by the CB₁ receptor (CB₁R), the most abundant G protein-coupled receptor (GPCR) in central nervous system (CNS) neurons, over by the AT₁R, which is one of the few G protein-coupled CNS receptors able to regulate cytoplasmic Ca²⁺ levels. A functional interaction suggesting a direct association between these receptors was detected. AT₁-CB₁ receptor heteromers (AT₁CB₁Hets) were identified in HEK-293T cells by bioluminescence resonance energy transfer (BRET²). Functional interactions within the AT₁-CB₁ complex and their potential relevance in Parkinson's disease (PD) were assessed. In situ proximity ligation assays (PLA) identified AT₁CB₁Hets in neurons, in which an important finding was that Ca²⁺ level increase upon AT₁R activation was reduced in the presence of cannabinoids acting on CB₁Rs. AT₁CB₁Het expression was quantified in samples from the 6-hydroxydopamine (6-OHDA) hemilesioned rat model of PD in which a lower expression of AT₁CB₁Hets was observed in striatal neurons from lesioned animals (versus non-lesioned). AT₁CB₁Het expression changed depending on both the lesion and the consequences of levodopa administration, i.e., dyskinesias versus lack of involuntary movements. A partial recovery in AT₁CB₁Het expression was detected in lesioned animals that developed levodopa-induced dyskinesias. These findings support the existence of a compensatory mechanism mediated by AT₁CB₁Hets that modulates susceptibility to levodopa-induced dyskinesias in PD. Therefore, cannabinoids may be useful in reducing calcium dyshomeostasis in dyskinesia.