Diabetes Research Group, BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada; Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Diabetes Research Group, BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada; Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Mol Metab. 2019 Mar;21:1-12. doi: 10.1016/j.molmet.2018.12.007. Epub 2018 Dec 24.
The divalent cation Calcium (Ca) regulates a wide range of processes in disparate cell types. Within insulin-producing β-cells, increases in cytosolic Ca directly stimulate insulin vesicle exocytosis, but also initiate multiple signaling pathways. Mediated through activation of downstream kinases and transcription factors, Ca-regulated signaling pathways leverage substantial influence on a number of critical cellular processes within the β-cell. Additionally, there is evidence that prolonged activation of these same pathways is detrimental to β-cell health and may contribute to Type 2 Diabetes pathogenesis.
This review aims to briefly highlight canonical Ca signaling pathways in β-cells and how β-cells regulate the movement of Ca across numerous organelles and microdomains. As a main focus, this review synthesizes experimental data from in vitro and in vivo models on both the beneficial and detrimental effects of Ca signaling pathways for β-cell function and health.
Acute increases in intracellular Ca stimulate a number of signaling cascades, resulting in (de-)phosphorylation events and activation of downstream transcription factors. The short-term stimulation of these Ca signaling pathways promotes numerous cellular processes critical to β-cell function, including increased viability, replication, and insulin production and secretion. Conversely, chronic stimulation of Ca signaling pathways increases β-cell ER stress and results in the loss of β-cell differentiation status. Together, decades of study demonstrate that Ca movement is tightly regulated within the β-cell, which is at least partially due to its dual roles as a potent signaling molecule.
二价阳离子钙（Ca）调节多种不同类型细胞的过程。在胰岛素分泌β细胞中，细胞浆内 Ca 的增加直接刺激胰岛素囊泡的胞吐作用，但也启动了多种信号通路。通过激活下游激酶和转录因子介导，Ca 调节的信号通路对β细胞内的许多关键细胞过程产生实质性影响。此外，有证据表明，这些相同通路的长期激活对β细胞的健康有害，并可能导致 2 型糖尿病的发病机制。
本篇综述旨在简要概述β细胞中的经典 Ca 信号通路，以及β细胞如何调节 Ca 在众多细胞器和微域中的运动。作为主要重点，本综述综合了来自体外和体内模型的实验数据，说明了 Ca 信号通路对β细胞功能和健康的有益和有害影响。
细胞内 Ca 的急性增加会刺激多种信号级联反应，导致（去）磷酸化事件和下游转录因子的激活。这些 Ca 信号通路的短期刺激促进了许多对β细胞功能至关重要的细胞过程，包括增加细胞活力、复制、胰岛素的产生和分泌。相反，Ca 信号通路的慢性刺激会增加β细胞内质网应激，导致β细胞分化状态的丧失。几十年来的研究表明，Ca 运动在β细胞内受到严格调控，这至少部分归因于 Ca 作为一种有效的信号分子的双重作用。
