Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor
Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor
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DOI：
10.1111/bph.13250
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发表时间：
2015-10-01
影响因子：
7.3
通讯作者：
Denovan-Wright, E. M.
中科院分区：
文献类型：
--
作者：
Laprairie, R. B.;Bagher, A. M.;Denovan-Wright, E. M.
背景和目的 据报道，大麻二酚可作为大麻素 CB1 受体的拮抗剂。我们假设大麻二酚会通过 CB1 受体的负变构调节来抑制大麻素激动剂活性。实验方法在异源表达 CB1 受体的 HEK 293A 细胞和内源表达 CB1 的纹状体神经元的 STHdh(Q7/Q7) 细胞模型中对 CB1 受体的内化、抑制蛋白 2 募集以及 PLC3 和 ERK1/2 磷酸化进行了定量受体。单独使用 2-花生四烯酰甘油或 (9)-四氢大麻酚，以及与不同浓度的大麻二酚组合处理细胞。 主要结果 大麻二酚可异源 (HEK 293A) 或内源性降低 2-花生四烯甘油和 (9)-四氢大麻酚对细胞中 PLC3 和 ERK1/2 依赖性信号传导的功效和效力(STHdh(Q7/Q7)) 表达 CB1 受体。通过减少 CB1 受体的抑制蛋白 2 募集，大麻二酚治疗可防止这些受体的内化。大麻二酚的变构活性取决于 CB1 受体胞外氨基末端第 98 和 107 位的极性残基。结论和含义大麻二酚表现为 CB1 受体的非竞争性负变构调节剂。变构调节与非 CB1 受体介导的效应相结合，可以解释大麻二酚的体内效应。 CB1 受体的变构调节剂具有治疗中枢神经系统和外周疾病的潜力，同时避免与这些受体的正位激动或拮抗相关的副作用。
Background and PurposeCannabidiol has been reported to act as an antagonist at cannabinoid CB1 receptors. We hypothesized that cannabidiol would inhibit cannabinoid agonist activity through negative allosteric modulation of CB1 receptors.Experimental ApproachInternalization of CB1 receptors, arrestin2 recruitment, and PLC3 and ERK1/2 phosphorylation, were quantified in HEK 293A cells heterologously expressing CB1 receptors and in the STHdh(Q7/Q7) cell model of striatal neurons endogenously expressing CB1 receptors. Cells were treated with 2-arachidonylglycerol or (9)-tetrahydrocannabinol alone and in combination with different concentrations of cannabidiol.Key Results Cannabidiolreduced the efficacy and potency of 2-arachidonylglycerol and (9)-tetrahydrocannabinol on PLC3- and ERK1/2-dependent signalling in cells heterologously (HEK 293A) or endogenously (STHdh(Q7/Q7)) expressing CB1 receptors. By reducing arrestin2 recruitment to CB1 receptors, cannabidiol treatment prevented internalization of these receptors. The allosteric activity of cannabidiol depended upon polar residues being present at positions 98 and 107 in the extracellular amino terminus of the CB1 receptor.Conclusions and ImplicationsCannabidiol behaved as a non-competitive negative allosteric modulator of CB1 receptors. Allosteric modulation, in conjunction with effects not mediated by CB1 receptors, may explain the in vivo effects of cannabidiol. Allosteric modulators of CB1 receptors have the potential to treat CNS and peripheral disorders while avoiding the adverse effects associated with orthosteric agonism or antagonism of these receptors.