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.
Competing Interests: Competing interests The authors declare no competing interests. Ethical approval Animal handling, sacrifice, and further experiments were conducted according to the guidelines set in Directive 2010/63/EU of the European Parliament and the Council of the European Union that are enforced in Spain by National and Regional organisms; the 3R rule (replace, refine, reduce) for animal experimentation was also considered. The rat PD model was generated and handled using a protocol approved by the Ethical Committee of the University of Santiago de Compostela (Protocol 14715012/2021/012; last revision 16 April 2021). According to the current legislation, protocol approval is unnecessary if animals are sacrificed to obtain a specific tissue as in this work to obtain primary neurons.
(© 2024. The Author(s).)