Fantini Jacques, Barrantes Francisco J
Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille (CRN2M), University of Aix-Marseille 2 and Aix-Marseille 3, CNRS UMR 6231, INRA USC 2027, Faculté des Sciences de St. Jérôme, Laboratoire des Interactions Moléculaires et Systèmes Membranaires, Marseille, France.
Biochim Biophys Acta. 2009 Nov;1788(11):2345-61. doi: 10.1016/j.bbamem.2009.08.016. Epub 2009 Sep 3.
Like all other monomeric or multimeric transmembrane proteins, receptors for neurotransmitters are surrounded by a shell of lipids which form an interfacial boundary between the protein and the bulk membrane. Among these lipids, cholesterol and sphingolipids have attracted much attention because of their well-known propensity to segregate into ordered platform domains commonly referred to as lipid rafts. In this review we present a critical analysis of the molecular mechanisms involved in the interaction of cholesterol/sphingolipids with neurotransmitter receptors, in particular acetylcholine and serotonin receptors, chosen as representative members of ligand-gated ion channels and G protein-coupled receptors. Cholesterol and sphingolipids interact with these receptors through typical binding sites located in both the transmembrane helices and the extracellular loops. By altering the conformation of the receptors ("chaperone-like" effect), these lipids can regulate neurotransmitter binding, signal transducing functions, and, in the case of multimeric receptors, subunit assembly and subsequent receptor trafficking to the cell surface. Several sphingolipids (especially gangliosides) also exhibit low/moderate affinity for neurotransmitters. We suggest that such lipids could facilitate (i) the attachment of neurotransmitters to the post-synaptic membrane and in some cases (ii) their subsequent delivery to specific protein receptors. Overall, various experimental approaches provide converging evidence that the biological functions of neurotransmitters and their receptors are highly dependent upon sphingolipids and cholesterol, which are active partners of synaptic transmission. Several decades of research have been necessary to untangle the skein of a complex network of molecular interactions between neurotransmitters, their receptors, cholesterol and sphingolipids. This sophisticated crosstalk between all four distinctive partners may allow a fine biochemical tuning of synaptic transmission.
与所有其他单体或多聚体跨膜蛋白一样，神经递质受体被一层脂质所包围，这些脂质在蛋白与整体膜之间形成了一个界面边界。在这些脂质中，胆固醇和鞘脂因其众所周知的倾向于聚集成通常被称为脂筏的有序平台结构域而备受关注。在这篇综述中，我们对胆固醇/鞘脂与神经递质受体相互作用所涉及的分子机制进行了批判性分析，特别选取了乙酰胆碱和5-羟色胺受体作为配体门控离子通道和G蛋白偶联受体的代表性成员。胆固醇和鞘脂通过位于跨膜螺旋和细胞外环中的典型结合位点与这些受体相互作用。通过改变受体的构象（“伴侣样”效应），这些脂质可以调节神经递质结合、信号转导功能，对于多聚体受体而言，还可以调节亚基组装以及随后受体向细胞表面的转运。几种鞘脂（尤其是神经节苷脂）对神经递质也表现出低/中等亲和力。我们认为，这类脂质可能有助于（i）神经递质附着于突触后膜，在某些情况下还有助于（ii）随后将其递送至特定的蛋白受体。总体而言，各种实验方法提供了一致的证据，表明神经递质及其受体的生物学功能高度依赖于鞘脂和胆固醇，它们是突触传递的活跃伙伴。解开神经递质、其受体、胆固醇和鞘脂之间复杂分子相互作用网络的谜团需要数十年的研究。这四种独特伙伴之间这种复杂的相互作用可能允许对突触传递进行精细的生化调节。
