BACKGROUND Insulin is stored within large dense-core granules in pancreatic beta (β)-cells and is released by Ca2+-triggered exocytosis with increasing blood glucose levels. Polarized and targeted secretion of insulin from β-cells in pancreatic islets into the vasculature has been proposed; however, the mechanisms related to cellular and molecular localization remain largely unknown. Within nerve terminals, the Ca2+-dependent release of a polarized transmitter is limited to the active zone, a highly specialized area of the presynaptic membrane. Several active zone-specific proteins have been characterized; among them, the CAST/ELKS protein family members have the ability to form large protein complexes with other active zone proteins to control the structure and function of the active zone for tight regulation of neurotransmitter release. Notably, ELKS but not CAST is also expressed in β-cells, implying that ELKS may be involved in polarized insulin secretion from β-cells. SCOPE OF REVIEW This review provides an overview of the current findings regarding the role(s) of ELKS and other active zone proteins in β-cells and focuses on the molecular mechanism underlying ELKS regulation within polarized insulin secretion from islets. MAJOR CONCLUSIONS ELKS localizes at the vascular-facing plasma membrane of β-cells in mouse pancreatic islets. ELKS forms a potent insulin secretion complex with L-type voltage-dependent Ca2+ channels on the vascular-facing plasma membrane of β-cells, enabling polarized Ca2+ influx and first-phase insulin secretion from islets. This model provides novel insights into the functional polarity observed during insulin secretion from β-cells within islets at the molecular level. This active zone-like region formed by ELKS at the vascular side of the plasma membrane is essential for coordinating physiological insulin secretion and may be disrupted in diabetes.

中文翻译：

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活性区蛋白ELKS在胰腺β细胞分泌胰岛素中的作用。

背景技术胰岛素储存在胰腺β（β）细胞的大密集核颗粒中，并通过Ca2 +触发的胞吐作用随血糖水平的升高而释放。已经提出了从胰岛的β细胞向血管中极化和靶向分泌胰岛素的方法。然而，与细胞和分子定位有关的机制仍然未知。在神经末梢内，极化递质的Ca2 +依赖性释放被限制在活动区，即突触前膜的高度专门化区域。已经鉴定了几种活性区特异性蛋白。其中，CAST / ELKS蛋白家族成员具有与其他活性区蛋白形成大蛋白复合物的能力，从而可以控制活性区的结构和功能以严格调节神经递质的释放。值得注意的是 ELKS但不是CAST也表达在β细胞中，这意味着ELKS可能参与了β细胞极化胰岛素的分泌。综述的范围该综述概述了有关ELKS和其他活性区蛋白在β细胞中的作用的当前发现，并着重于胰岛极化胰岛素分泌中ELKS调控的分子机制。主要结论ELKS位于小鼠胰岛β细胞的面向血管的质膜上。ELKS在β细胞面向血管的质膜上与L型电压依赖性Ca2 +通道形成有效的胰岛素分泌复合物，从而使极化的Ca2 +流入和从胰岛分泌出第一相胰岛素。该模型提供了从胰岛内的β细胞在分子水平上胰岛素分泌过程中观察到的功能极性的新见解。由ELKS在质膜血管侧形成的这种活动区状区域对于协调生理性胰岛素分泌至关重要，在糖尿病中可能会破坏。