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.

钙离子 （Ca²⁺） 稳态对神经元功能和神经传递至关重要。本研究的重点是 CB₁ 受体 （CB₁R） 介导的作用，CB 1 受体是中枢神经系统 （CNS） 神经元中最丰富的 G 蛋白偶联受体 （GPCR），而 AT₁R 是少数能够调节细胞质 Ca²⁺ 水平的 G 蛋白偶联 CNS 受体之一。检测到表明这些受体之间直接相关的功能相互作用。通过生物发光共振能量转移 （BRET²） 在 HEK-293T 细胞中鉴定出 AT_{1-CB 1} 受体异聚体 （AT₁CB₁Hets）。评估了 AT_{1-CB 1} 复合物内的功能相互作用及其在帕金森病 （PD） 中的潜在相关性。原位邻位连接测定 （PLA） 在神经元中鉴定了 AT₁CB₁Hets，其中一项重要发现是，在作用于 CB₁Rs 的大麻素存在下，AT₁R 激活时 Ca²⁺ 水平的增加减少。在来自 PD 的 6-羟基多巴胺 （6-OHDA） 血统大鼠模型的样品中定量 AT₁CB₁Het 表达，其中 AT₁CB₁ 的表达较低在受损动物的纹状体神经元中观察到 Hets （与非病变动物相比）。AT₁CB₁Het 表达根据病变和左旋多巴给药的后果而变化，即运动障碍与缺乏不自主运动。在发生左旋多巴诱导的运动障碍的病变动物中检测到 AT₁CB₁Het 表达的部分恢复。 这些发现支持存在由 AT₁CB₁Hets 介导的代偿机制，该机制调节 PD 中对左旋多巴诱导的运动障碍的易感性。因此，大麻素可能有助于减少运动障碍中的钙稳态。