Department of Medicine, University of California Irvine, School of Medicine, Irvine, California, United States of America.
PLoS One. 2013 Jun 11;8(6):e65711. doi: 10.1371/journal.pone.0065711. Print 2013.
Neuroligin-2 is a transmembrane, cell-surface protein originally identified as an inhibitory synapse-associated protein in the central nervous system. Neuroligin-2 is also present on the pancreatic beta-cell surface, and there it engages in transcellular interactions that drive functional maturation of the insulin secretory machinery; these are necessary for normal insulin secretion. The effects of neuroligin-2 deficiency on brain and neuronal function and morphology and on behavior and coordination have been extensively characterized using neuroligin-2 knockout mice. The effects of absent neuroligin-2 expression on islet development and function, however, are unknown. Here, to help test whether neuroligin-2 is necessary for normal islet development, we characterized islet morphology in mice lacking neuroligin-2. To test whether-as predicted by our earlier co-culture studies-absence of neuroligin-2 impairs beta cell function, we compared glucose-stimulated insulin secretion by islets from mutant and wild-type mice. Our results show that while islets from neuroligin-2-deficient mice do not to appear to differ architecturally from wild-type islets, they are smaller, fewer in number, and contain beta cells with lower insulin content. Evaluation of transcript levels suggests that upregulation of neuroligin-1 helps compensate for loss of neuroligin-2. Surprisingly, under both basal and stimulating glucose levels, isolated islets from the knockout mice secreted more of their intracellular insulin content. Rat islets with shRNA-mediated neuroligin-2 knockdown also exhibited increased insulin secretion. Neurexin transcript levels were lower in the knockout mice and, consistent with our prior finding that neurexin is a key constituent of the insulin granule docking machinery, insulin granule docking was reduced. These results indicate that neuroligin-2 is not necessary for the formation of pancreatic islets but that neuroligin-2 influences islet size and number. Neuroligin-2-perhaps through its effects on the expression and/or activity of its binding partner neurexin-promotes insulin granule docking, a known constraint on insulin secretion.
神经黏附素-2 是一种跨膜细胞表面蛋白，最初在中枢神经系统中被鉴定为抑制性突触相关蛋白。神经黏附素-2 也存在于胰腺β细胞表面，在那里它参与细胞间相互作用，驱动胰岛素分泌机制的功能成熟；这对于正常的胰岛素分泌是必要的。使用神经黏附素-2 敲除小鼠，广泛研究了神经黏附素-2 缺乏对大脑和神经元功能和形态以及行为和协调的影响。然而，神经黏附素-2 表达缺失对胰岛发育和功能的影响尚不清楚。在这里，为了帮助测试神经黏附素-2 是否对正常胰岛发育是必需的，我们对缺乏神经黏附素-2 的小鼠胰岛形态进行了特征描述。为了测试是否如我们之前的共培养研究所预测的那样，神经黏附素-2 的缺失会损害β细胞功能，我们比较了突变型和野生型小鼠胰岛的葡萄糖刺激胰岛素分泌。我们的结果表明，尽管缺乏神经黏附素-2 的小鼠胰岛在结构上似乎与野生型胰岛没有差异，但它们更小、数量更少，并且含有胰岛素含量较低的β细胞。转录水平的评估表明，神经黏附素-1 的上调有助于弥补神经黏附素-2 的缺失。令人惊讶的是，在基础和刺激葡萄糖水平下，从敲除小鼠分离的胰岛分泌了更多的细胞内胰岛素含量。用 shRNA 介导的神经黏附素-2 敲低的大鼠胰岛也表现出增加的胰岛素分泌。敲除小鼠中的神经连接蛋白转录水平较低，与我们之前的发现一致，即神经连接蛋白是胰岛素颗粒停泊机制的关键组成部分，胰岛素颗粒停泊减少。这些结果表明，神经黏附素-2 对于胰腺胰岛的形成不是必需的，但神经黏附素-2 影响胰岛的大小和数量。神经黏附素-2-可能通过其对结合伴侣神经连接蛋白的表达和/或活性的影响-促进胰岛素颗粒停泊，这是胰岛素分泌的已知限制。
