Abstract
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.