Nicolussi Simon, Gertsch Jürg
Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, Bern, Switzerland.
Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, Bern, Switzerland.
Vitam Horm. 2015;98:441-85. doi: 10.1016/bs.vh.2014.12.011. Epub 2015 Feb 27.
Endocannabinoids are arachidonic acid-derived endogenous lipids that activate the endocannabinoid system which plays a major role in health and disease. The primary endocannabinoids are anandamide (AEA, N-arachidonoylethanolamine) and 2-arachidonoyl glycerol. While their biosynthesis and metabolism have been studied in detail, it remains unclear how endocannabinoids are transported across the cell membrane. In this review, we critically discuss the different models of endocannabinoid trafficking, focusing on AEA cellular uptake which is best studied. The evolution of the current knowledge obtained with different AEA transport inhibitors is reviewed and the confusions caused by the lack of their specificity discussed. A comparative summary of the most important AEA uptake inhibitors and the studies involving their use is provided. Based on a comprehensive literature analysis, we propose a model of facilitated AEA membrane transport followed by intracellular shuttling and sequestration. We conclude that novel and more specific probes will be essential to identify the missing targets involved in endocannabinoid membrane transport.
内源性大麻素是源自花生四烯酸的内源性脂质，可激活内源性大麻素系统，该系统在健康和疾病中发挥着重要作用。主要的内源性大麻素是花生四烯酸乙醇胺（AEA，N-花生四烯酰乙醇胺）和2-花生四烯酰甘油。虽然它们的生物合成和代谢已得到详细研究，但内源性大麻素如何跨细胞膜转运仍不清楚。在本综述中，我们批判性地讨论了内源性大麻素转运的不同模型，重点关注研究最为充分的AEA细胞摄取。回顾了使用不同AEA转运抑制剂所获得的当前知识的演变，并讨论了由于缺乏特异性而导致的混淆。提供了最重要的AEA摄取抑制剂及其相关研究的比较总结。基于全面的文献分析，我们提出了一种促进AEA膜转运随后进行细胞内穿梭和隔离的模型。我们得出结论认为，新型且更具特异性的探针对于识别内源性大麻素膜转运中缺失的靶点至关重要。
