Institut des Biomolécules Max Mousseron, UMR 5247, Université Montpellier - CNRS, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France.
Walther Straub Institute for Pharmacology and Toxicology, Ludwig-Maximilians-Universität, Nußbaumstr. 26, 80336 Munich, Germany.
Neuropharmacology. 2017 Dec;127:196-223. doi: 10.1016/j.neuropharm.2017.06.011. Epub 2017 Jun 13.
The nicotinic acetylcholine receptor (nAChR) represents the prototype of ligand-gated ion channels. It is vital for neuromuscular transmission and an important regulator of neurotransmission. A variety of toxic compounds derived from diverse species target this receptor and have been of elemental importance in basic and applied research. They enabled milestone discoveries in pharmacology and biochemistry ranging from the original formulation of the receptor concept, the first isolation and structural analysis of a receptor protein (the nAChR) to the identification, localization, and differentiation of its diverse subtypes and their validation as a target for therapeutic intervention. Among the venom-derived compounds, α-neurotoxins and α-conotoxins provide the largest families and still represent indispensable pharmacological tools. Application of modified α-neurotoxins provided substantial structural and functional details of the nAChR long before high resolution structures were available. α-bungarotoxin represents not only a standard pharmacological tool and label in nAChR research but also for unrelated proteins tagged with a minimal α-bungarotoxin binding motif. A major advantage of α-conotoxins is their smaller size, as well as superior selectivity for diverse nAChR subtypes that allows their development into ligands with optimized pharmacological and chemical properties and potentially novel drugs. In the following, these two groups of nAChR antagonists will be described focusing on their respective roles in the structural and functional characterization of nAChRs and their development into research tools. In addition, we provide a comparative overview of the diverse α-conotoxin selectivities that can serve as a practical guide for both structure activity studies and subtype classification. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.'
烟碱型乙酰胆碱受体 (nAChR) 是配体门控离子通道的典型代表。它对神经肌肉传递至关重要，也是神经递质传递的重要调节剂。来自不同物种的多种毒性化合物靶向该受体，在基础和应用研究中具有重要意义。它们使药理学和生物化学领域取得了里程碑式的发现，从受体概念的最初提出、第一个受体蛋白（nAChR）的分离和结构分析，到其多种亚型的鉴定、定位和分化，以及将其作为治疗干预靶点的验证。在这些毒液衍生的化合物中，α-神经毒素和α-芋螺毒素提供了最大的家族，仍然是不可或缺的药理学工具。修饰后的α-神经毒素的应用提供了 nAChR 的大量结构和功能细节，而此时高分辨率结构还不可用。α-银环蛇毒素不仅是 nAChR 研究中的标准药理学工具和标记物，也是与最小 α-银环蛇毒素结合基序标记的不相关蛋白的标记物。α-芋螺毒素的一个主要优势是其体积小，对不同 nAChR 亚型的选择性更高，这使得它们能够开发成具有优化的药理学和化学性质的配体，以及具有潜在新颖性的药物。在下面的内容中，将描述这两类 nAChR 拮抗剂，重点介绍它们在 nAChR 的结构和功能特征描述以及作为研究工具的开发中的各自作用。此外，我们还提供了不同 α-芋螺毒素选择性的比较概述，这可以作为结构活性研究和亚型分类的实用指南。本文是专题“毒液衍生肽作为药理学工具”的一部分。
