Black widow spider α-latrotoxin:: a presynaptic neurotoxin that shares structural homology with the glucagon-like peptide-1 family of insulin secretagogic hormones
Black widow spider α-latrotoxin:: a presynaptic neurotoxin that shares structural homology with the glucagon-like peptide-1 family of insulin secretagogic hormones
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DOI：
10.1016/s0305-0491(98)10088-3
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发表时间：
1998-10-01
影响因子：
2.2
通讯作者：
Habener, JF
中科院分区：
文献类型：
--
作者：
Holz, GG;Habener, JF
α-蛇麻毒素是从黑寡妇蜘蛛Latrodectus tredecimguttatus的毒液中分离的突触前神经毒素。它通过使神经元去极化、增加[Ca 2 +]（i）和刺激神经末梢神经递质的不受控制的胞吐作用，在脊椎动物中枢神经系统中发挥毒性作用。α-latrotoxin的作用部分由称为GIRL或latrophilin的GTP结合蛋白偶联受体介导。毒蜥外泌肽-4也是一种毒液毒素，它来源于毒蜥的唾液腺。作为胰高血糖素样肽-1（7-36）-酰胺（GLP-1）受体的激动剂，从而刺激胰岛β细胞分泌胰岛素。本文报道了α-latrotoxin和毒蜥外泌肽-4之间令人惊讶的结构同源性，其在促分泌激素的GLP-1样家族（GLP-1、胰高血糖素、血管活性肠多肽、胰泌素、垂体腺苷酸环化酶激活多肽）的所有成员中也是明显的。在这种同源性的基础上，我们报告了一种嵌合肽（黑寡妇GLP-1）的合成和初步表征，该肽可刺激人类β细胞和MIN 6胰岛素瘤细胞中的Ca 2+信号传导和胰岛素分泌。本文还报道了α-latrotoxin和exendin-4的GTP结合蛋白偶联受体在其细胞外定向的氨基末端具有高度显著的结构相似性。我们建议，分子模拟产生了保守的结构基序的分泌毒素及其受体，从而解释了进化的防御或捕食策略，共享之间的远亲物种，包括蜘蛛，蜥蜴和蛇。显然，α-latrotoxin和exendin-4的毒性作用是通过它们与CTP结合蛋白偶联受体相互作用的能力来解释的，CTP结合蛋白偶联受体通常介导内源性激素或神经肽的作用。(C)1998年爱思唯尔科学公司All rights reserved.
alpha-Latrotoxin is a presynaptic neurotoxin isolated from the venom of the black widow spider Latrodectus tredecimguttatus. It exerts toxic effects in the vertebrate central nervous system by depolarizing neurons, by increasing [Ca2+](i) and by stimulating uncontrolled exocytosis of neurotransmitters from nerve terminals. The actions of alpha-latrotoxin are mediated, in part, by a GTP-binding protein-coupled receptor referred to as GIRL or latrophilin. Exendin-4 is also a venom toxin, and it is derived from the salivary gland of the Gila monster Heloderma suspectum. It acts as an agonist at the receptor for glucagon-like peptide-1(7-36)-amide (GLP-1), thereby stimulating secretion of insulin from pancreatic beta-cells of the islets of Langerhans. Here is reported a surprising structural homology between alpha-latrotoxin and exendin-4 that is also apparent amongst all members of the GLP-l-like family of secretagogic hormones (GLP-1, glucagon, vasoactive intestinal polypeptide, secretin, pituitary adenylyl cyclase activating polypeptide). On the basis of this homology, we report the synthesis and initial characterization of a chimeric peptide (Black Widow GLP-1) that stimulates Ca2+ signaling and insulin secretion in human beta-cells and MIN6 insulinoma cells. It is also reported here that the GTP-binding protein-coupled receptors for alpha-latrotoxin and exendin-4 share highly significant structural similarity in their extracellularly-oriented amino-termini. We propose that molecular mimicry has generated conserved structural motifs in secretagogic toxins and their receptors, thereby explaining the evolution of defense or predatory strategies that are shared in common amongst distantly related species including spiders, lizards, and snakes. Evidently, the toxic effects of alpha-latrotoxin and exendin-4 are explained by their ability to interact with CTP-binding protein-coupled receptors that normally mediate the actions of endogenous hormones or neuropeptides. (C) 1998 Elsevier Science Inc. All rights reserved.