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

Calcium ion (Ca 2+ ) homeostasis is crucial for neuron function and neurotransmission. This study focused on the actions mediated by the CB 1 receptor (CB 1 R), the most abundant G protein-coupled receptor (GPCR) in central nervous system (CNS) neurons, over by the AT 1 R, which is one of the few G protein-coupled CNS receptors able to regulate cytoplasmic Ca 2+ levels. A functional interaction suggesting a direct association between these receptors was detected. AT 1 -CB 1 receptor heteromers (AT 1 CB 1 Hets) were identified in HEK-293T cells by bioluminescence resonance energy transfer (BRET 2 ). Functional interactions within the AT 1 -CB 1 complex and their potential relevance in Parkinson’s disease (PD) were assessed. In situ proximity ligation assays (PLA) identified AT 1 CB 1 Hets in neurons, in which an important finding was that Ca 2+ level increase upon AT 1 R activation was reduced in the presence of cannabinoids acting on CB 1 Rs. AT 1 CB 1 Het expression was quantified in samples from the 6-hydroxydopamine (6-OHDA) hemilesioned rat model of PD in which a lower expression of AT 1 CB 1 Hets was observed in striatal neurons from lesioned animals (versus non-lesioned). AT 1 CB 1 Het 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 AT 1 CB 1 Het expression was detected in lesioned animals that developed levodopa-induced dyskinesias. These findings support the existence of a compensatory mechanism mediated by AT 1 CB 1 Hets that modulates susceptibility to levodopa-induced dyskinesias in PD. Therefore, cannabinoids may be useful in reducing calcium dyshomeostasis in dyskinesia.