Department of Biomedical Sciences, University of Teramo, Italy.
Curr Med Chem. 2010;17(14):1487-99. doi: 10.2174/092986710790980087.
Cellular signaling is regulated by several biochemical reactions, whose dynamics depends on changes in the fluxes of specific ligands through the containment barriers that are the biological membranes. The regulation of this complex dynamic equilibrium is mainly due to the activity of border proteins, that must be able to interact simultaneously with the lipid bilayer and the extracellular milieu. Endocannabinoid receptors, that include type-1 and type-2 cannabinoid receptors, the transient vanilloid potential receptors and the peroxisome proliferator-activated receptors, represent one of the most intriguing examples of "border" proteins. They have also been identified as important drug discovery targets with potential therapeutic applications, from antiemesis, appetite enhancement, analgesia, glaucoma treatment, and immune suppression. However, as yet the molecular details of endocannabinoid receptor regulation remain elusive. In this review we summarize the most relevant aspects of the structural/functional characterization of these receptors, with a focus on the active role played by biological membranes (in particular lipid rafts) in the modulation of their accessibility and mode of ligand binding. Based on available evidence, we propose that endocannabinoid receptors can be regulated by the rate of interlayer exchange and lateral diffusion of endocannabinoid/cholesterol complexes within lipid bilayers, thus suggesting innovative approaches for the therapeutic exploitation of the membrane component of endocannabinoid signaling.
细胞信号受多种生化反应调控，其动态变化取决于特定配体通过生物膜（即细胞膜）的限制屏障的通量变化。这种复杂动态平衡的调节主要归因于边界蛋白的活性，这些蛋白必须能够同时与脂双层和细胞外环境相互作用。内源性大麻素受体（包括 1 型和 2 型大麻素受体、瞬时香草素受体和过氧化物酶体增殖物激活受体）是“边界”蛋白的最有趣的例子之一。它们也被确定为具有潜在治疗应用的重要药物发现靶点，可用于止吐、增强食欲、镇痛、治疗青光眼和免疫抑制等。然而，内源性大麻素受体调节的分子细节仍然难以捉摸。在这篇综述中，我们总结了这些受体的结构/功能特征的最相关方面，重点介绍了生物膜（特别是脂筏）在调节其可及性和配体结合模式方面的积极作用。基于现有证据，我们提出内源性大麻素受体可以通过内源性大麻素/胆固醇复合物在脂质双层中的夹层交换和横向扩散速率来调节，从而为内源性大麻素信号的膜成分的治疗利用提出了创新方法。
