Department of Medicine and Pediatric Diabetes Research Center, UCSD School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
J Biol Chem. 2012 Jun 8;287(24):19816-26. doi: 10.1074/jbc.M111.280537. Epub 2012 Apr 23.
Normal glucose-stimulated insulin secretion is dependent on interactions between neighboring β cells. Elucidation of the reasons why this cell-to-cell contact is essential will probably yield critical insights into β cell maturation and function. In the central nervous system, transcellular protein interactions (i.e. interactions between proteins on the surfaces of different cells) involving neuroligins are key mediators of synaptic functional development. We previously demonstrated that β cells express neuroligin-2 and that insulin secretion is affected by changes in neuroligin-2 expression. Here we show that the effect of neuroligin-2 on insulin secretion is mediated by transcellular interactions. Neuroligin-2 binds with nanomolar affinity to a partner on the β cell surface and contributes to the increased insulin secretion brought about by β cell-to-β cell contact. It does so in a manner seemingly independent of interactions with neurexin, a known binding partner. As in the synapse, transcellular neuroligin-2 interactions enhance the functioning of the submembrane exocytic machinery. Also, as in the synapse, neuroligin-2 clustering is important. Neuroligin-2 in soluble form, rather than presented on a cell surface, decreases insulin secretion by rat islets and MIN-6 cells, most likely by interfering with endogenous neuroligin interactions. Prolonged contact with neuroligin-2-expressing cells increases INS-1 β cell proliferation and insulin content. These results extend the known parallels between the synaptic and β cell secretory machineries to extracellular interactions. Neuroligin-2 interactions are one of the few transcellular protein interactions thus far identified that directly enhance insulin secretion. Together, these results indicate a significant role for transcellular neuroligin-2 interactions in the establishment of β cell function.
正常的葡萄糖刺激胰岛素分泌依赖于相邻β细胞之间的相互作用。阐明这种细胞间接触至关重要的原因，可能会深入了解β细胞的成熟和功能。在中枢神经系统中，涉及神经连接蛋白的跨细胞蛋白相互作用（即不同细胞表面上的蛋白质之间的相互作用）是突触功能发育的关键介质。我们之前证明β细胞表达神经连接蛋白-2，并且胰岛素分泌受神经连接蛋白-2表达变化的影响。在这里，我们表明神经连接蛋白-2对胰岛素分泌的影响是通过细胞间相互作用介导的。神经连接蛋白-2以纳摩尔亲和力与β细胞表面上的一个伴侣结合，并有助于β细胞与β细胞接触引起的胰岛素分泌增加。它以一种与已知结合伴侣神经连接蛋白相互作用似乎无关的方式做到这一点。与突触一样，跨细胞神经连接蛋白-2相互作用增强了亚膜出胞机制的功能。同样，与突触一样，神经连接蛋白-2的聚类很重要。以可溶性形式而不是在细胞表面呈现的神经连接蛋白-2会降低大鼠胰岛和 MIN-6 细胞的胰岛素分泌，这很可能是通过干扰内源性神经连接蛋白相互作用来实现的。与表达神经连接蛋白-2的细胞长时间接触会增加 INS-1β细胞的增殖和胰岛素含量。这些结果将已知的突触和β细胞分泌机制之间的相似之处扩展到细胞外相互作用。神经连接蛋白-2相互作用是迄今为止鉴定出的少数几种直接增强胰岛素分泌的跨细胞蛋白相互作用之一。这些结果表明，跨细胞神经连接蛋白-2相互作用在β细胞功能的建立中起着重要作用。
