大麻素CB1受体激活减轻n -甲基-d-天冬氨酸受体介导的神经毒性

IF 3.7 Q1 CHEMISTRY, MEDICINAL
Gemma Navarro*, Iu Raïch, Joan Biel Rebassa, Jaume Lillo, Catalina Pérez-Olives, Toni Capó, Erik Cubeles, Carlos A. Saura, Arnau Cordomí, Eddy Sotelo, Irene Reyes-Resina and Rafael Franco*, 
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引用次数: 0

摘要

阿尔茨海默病(AD)的特点是突触功能障碍和兴奋性毒性,但有效的治疗策略仍然有限。本研究探讨了大麻素CB1受体(CB1Rs)和n -甲基-d-天冬氨酸受体(NMDARs)之间的功能和物理相互作用,这些相互作用与AD病理有关。利用HEK-293T细胞的生物发光共振能量转移和成像分析,我们证明了CB1R与NMDAR的N1亚基之间的直接相互作用,支持受体复合物的形成。功能分析进一步揭示了双向负串扰:NMDA减弱CB1R介导的cAMP抑制,而CB1R激活降低NMDA诱导的钙内流和丝裂原激活的蛋白激酶信号通路激活。这种负面的串扰表明存在与功能后果的受体-受体相互作用。NMDARs的CB1Rs复合物和N1亚基复合物存在于神经元和小胶质细胞中,它们的表达在Aβ1-42和来自APPSw/Ind AD模型小鼠的细胞中上调。然而,上调并不总是与更强的CB1R-NMDAR交叉调制相关,这表明细胞特异性信号体组成决定了信号传导的结果。在功能上,CB1R激活具有神经保护作用:它可以挽救由NMDA和Aβ1-42诱导的神经突损失,突出了调节CB1R - nmdar相互作用的治疗潜力。这些发现支持CB1R-NMDAR相互作用的模型,通过动态功能交叉调节,精细调节兴奋毒性和炎症信号通路。这一机制为解决大麻素-谷氨酸相互作用提供了治疗前景。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Cannabinoid CB1 Receptor Activation Mitigates N-Methyl-d-aspartate Receptor-Mediated Neurotoxicity

Alzheimer’s disease (AD) is characterized by synaptic dysfunction and excitotoxicity, yet effective therapeutic strategies remain limited. This study explores the functional and physical interplay between cannabinoid CB1 receptors (CB1Rs) and N-methyl-d-aspartate receptors (NMDARs), which are implicated in AD pathology. Using bioluminescence resonance energy transfer and imaging assays in HEK-293T cells, we demonstrate a direct interaction between CB1R and the N1 subunit of NMDAR, supporting the formation of receptor complexes. Functional assays further reveal a bidirectional negative crosstalk: NMDA attenuates CB1R-mediated cAMP inhibition, while CB1R activation reduces NMDA-induced calcium influx and mitogen-activated protein kinase signaling pathway activation. This negative crosstalk suggests the existence of receptor–receptor interactions with functional consequences. Complexes of CB1Rs and N1 subunits of NMDARs are present in both neurons and microglia, and their expression is upregulated in response to Aβ1–42 and in cells derived from the APPSw/Ind AD model mice. However, upregulation did not always correlate with stronger CB1R–NMDAR cross-modulation, suggesting that cell-specific signalosome composition shapes the signaling outcome. Functionally, CB1R activation confers neuroprotection: It rescues neurite loss induced by NMDA and Aβ1–42, highlighting the therapeutic potential of modulating CB1R–NMDAR interactions. These findings support a model in which CB1R–NMDAR interactions, through dynamic functional cross-modulation, finely tune excitotoxic and inflammatory signaling pathways. This mechanism offers therapeutic prospects for addressing cannabinoid-glutamatergic interactions.

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来源期刊
ACS Pharmacology and Translational Science
ACS Pharmacology and Translational Science Medicine-Pharmacology (medical)
CiteScore
10.00
自引率
3.30%
发文量
133
期刊介绍: ACS Pharmacology & Translational Science publishes high quality, innovative, and impactful research across the broad spectrum of biological sciences, covering basic and molecular sciences through to translational preclinical studies. Clinical studies that address novel mechanisms of action, and methodological papers that provide innovation, and advance translation, will also be considered. We give priority to studies that fully integrate basic pharmacological and/or biochemical findings into physiological processes that have translational potential in a broad range of biomedical disciplines. Therefore, studies that employ a complementary blend of in vitro and in vivo systems are of particular interest to the journal. Nonetheless, all innovative and impactful research that has an articulated translational relevance will be considered. ACS Pharmacology & Translational Science does not publish research on biological extracts that have unknown concentration or unknown chemical composition. Authors are encouraged to use the pre-submission inquiry mechanism to ensure relevance and appropriateness of research.
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