Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor
Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor
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DOI：
10.1073/pnas.1202906109
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发表时间：
2012-12-18
影响因子：
11.1
通讯作者：
Takahashi, Reinaldo N.
中科院分区：
文献类型：
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作者：
Pamplona, Fabricio A.;Ferreira, Juliano;Takahashi, Reinaldo N.
G蛋白偶联受体的变构调节代表了当前药理学的关键目标。特别是，内源性变构调节剂可能代表旨在最大化治疗效果和减少药物副作用的干预措施的重要靶点。在这里，我们表明抗炎脂质脂氧素A（4）是CB 1大麻素受体的内源性变构增强剂。在脑组织中检测到脂氧素A（4），不竞争CB 1受体的正构结合位点（与H-3-SR 141716 A相比），也不改变内源性大麻素代谢（与URB 597和MAFP相比），但它增强了大麻素对CB 1受体的亲和力，从而增强了这种内源性大麻素在体外和体内的作用。此外，脂氧素A（4）对β-淀粉样蛋白（1-40）诱导的小鼠空间记忆障碍具有CB 1受体依赖性保护作用。脂氧素作为一类CB 1受体的内源性变构调节剂的发现可以促进内源性大麻素系统的治疗开发，特别是用于治疗神经退行性疾病。
Allosteric modulation of G-protein-coupled receptors represents a key goal of current pharmacology. In particular, endogenous allosteric modulators might represent important targets of interventions aimed at maximizing therapeutic efficacy and reducing side effects of drugs. Here we show that the anti-inflammatory lipid lipoxin A(4) is an endogenous allosteric enhancer of the CB1 cannabinoid receptor. Lipoxin A(4) was detected in brain tissues, did not compete for the orthosteric binding site of the CB1 receptor (vs. H-3-SR141716A), and did not alter endocannabinoid metabolism (as opposed to URB597 and MAFP), but it enhanced affinity of anandamide at the CB1 receptor, thereby potentiating the effects of this endocannabinoid both in vitro and in vivo. In addition, lipoxin A(4) displayed a CB1 receptor-dependent protective effect against beta-amyloid (1-40)-induced spatial memory impairment in mice. The discovery of lipoxins as a class of endogenous allosteric modulators of CB1 receptors may foster the therapeutic exploitation of the endocannabinoid system, in particular for the treatment of neurodegenerative disorders.