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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Identification of a high-affinity binding site involved in the transport of endocannabinoids.
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Identification of a high-affinity binding site involved in the transport of endocannabinoids.

机译：鉴定涉及内源性大麻素运输的高亲和力结合位点。

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摘要

Phytocannabinoids, such as the principal bioactive component of marijuana, delta9-tetrahydrocannabinol, have been used for thousands of years for medical and recreational purposes. delta9-Tetrahydrocannabinol and endogenous cannabinoids (e.g., anandamide) initiate their agonist properties by stimulating the cannabinoid family of G protein-coupled receptors (CB1 and CB2). The biosynthesis and physiology of anandamide is well understood, but its mechanism of uptake (resulting in signal termination by fatty acid amide hydrolase) has been elusive. Mounting evidence points to the existence of a specific anandamide transport protein; however, no direct evidence for this protein has been provided. Here, we use a potent, competitive small molecule inhibitor of anandamide uptake (LY2318912, IC50 7.27 +/- 0.510 nM) to identify a high-affinity, saturable anandamide transporter binding site (LY2318912; K(d) = 7.62 +/- 1.18 nM, B(max) = 31.6 +/- 1.80 fmol/mg protein) that is distinct from fatty acid amide hydrolase. Systemic administration of the inhibitor into rodents elevates anandamide levels 5-fold in the brain and demonstrates efficacy in the formalin paw-licking model of persistent pain with no obvious adverse effects on motor function. Identification of the anandamide transporter binding site resolves a missing mechanistic link in endocannabinoid signaling, and in vivo results suggest that endocannabinoid transporter antagonists may provide a strategy for positive modulation of cannabinoid receptors.
机译：大麻素，例如大麻的主要生物活性成分，delta9-四氢大麻酚，已被用于医疗和娱乐目的数千年。 δ9-四氢大麻酚和内源性大麻素（例如anandamide）通过刺激G蛋白偶联受体（CB1和CB2）的大麻素家族来启动其激动剂特性。花生四烯酸酰胺的生物合成和生理学已广为人知，但其吸收机制（导致脂肪酸酰胺水解酶终止信号）一直难以捉摸。越来越多的证据表明存在特定的anandamide转运蛋白。但是，没有提供这种蛋白质的直接证据。在这里，我们使用一种有效的竞争性小分子抑制剂，抑制Anandamide摄取（LY2318912，IC50 7.27 +/- 0.510 nM），以鉴定出高亲和力的，饱和的Anandamide转运蛋白结合位点（LY2318912; K（d）= 7.62 +/- 1.18 nM，B（max）= 31.6 +/- 1.80 fmol / mg蛋白），不同于脂肪酸酰胺水解酶。抑制剂在啮齿动物中的全身给药可使大脑中的anandamide水平升高5倍，并证明在持续性疼痛的福尔马林舔舔模型中具有功效，而对运动功能无明显不利影响。 anandamide转运蛋白结合位点的鉴定解决了内源性大麻素信号传导中缺失的机械联系，体内结果表明内源性大麻素转运蛋白拮抗剂可能为大麻素受体的正调节提供了策略。

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