Na+/Ca2+ Exchange and the Plasma Membrane Ca2+-ATPase in β-Cell Function and Diabetes
Na+/Ca2+ Exchange and the Plasma Membrane Ca2+-ATPase in β-Cell Function and Diabetes
复制标题
DOI：
10.1007/978-1-4614-4756-6_33
复制
发表时间：
2013-01-01
期刊：
影响因子：
--
通讯作者：
Pachera, Nathalie
中科院分区：
文献类型：
--
作者：
Herchuelz, Andre;Nguidjoe, Evrard;Pachera, Nathalie
大鼠胰腺β细胞表达Na+/Ca2+交换器1 (NCX1)的两种剪接变体和质膜Ca2+-ATP酶(PMCA)的六种剪接变体。在 β 细胞中，Na+/Ca2+ 交换表现出高容量，有助于 Ca2+ 流出和流动，并参与胰岛素释放的控制。功能获得研究表明，NCX1 或 PMCA2 的过度表达会导致内质网 (ER) Ca2+ 耗竭，随后出现 ER 应激、β 细胞增殖减少以及 β 细胞因凋亡而死亡。有趣的是，长期暴露于细胞因子或高浓度游离脂肪酸也会诱导糖尿病患者内质网 Ca2+ 耗竭和 β 细胞死亡。相反，功能丧失研究表明，NCX1 (Ncx1(+/-)) 的杂合失活会导致 β 细胞功能（胰岛素产生和释放）增强，并且 β 细胞质量和增殖增加五倍。该突变还增强了 β 细胞对缺氧的抵抗力，当移植到糖尿病动物体内时，Ncx1(+/-) 胰岛的糖尿病治愈率比 Ncx1(+/+) 胰岛高四到七倍。因此，Na+/Ca2+交换体的下调会导致β细胞功能发生各种变化，这与糖尿病中常见的主要异常相反。此外，β细胞是一种可兴奋细胞，在NCX1的选择性剪接区域中包含互斥的外显子B，这赋予其NCX剪接变体（NCX1.3和1.7）对KB-R7943等化合物的抑制作用的高敏感性。这为预防和治疗糖尿病和胰岛移植后的β细胞功能障碍提供了独特的模型。
The rat pancreatic beta-cell expresses two splice variants of the Na+/Ca2+ exchanger 1 (NCX1) and six splice variants of the plasma membrane Ca2+-ATPase (PMCA). In the beta-cell, Na+/Ca2+ exchange displays a high capacity, contributes to both Ca2+ out flow and in flux and participates to the control of insulin release. Gain of function studies show that overexpression of NCX1 or PMCA2 leads to endoplasmic reticulum (ER) Ca2+ depletion with subsequent ER stress, decrease in beta-cell proliferation and beta-cell death by apoptosis. Interestingly, chronic exposure to cytokines or high free fatty acids concentration also induces ER Ca2+ depletion and beta-cell death in diabetes. Loss of function studies shows, on the contrary, that heterozygous inactivation of NCX1 (Ncx1(+/-)) leads to an increase in beta-cell function (insulin production and release) and a fivefold increase in both beta-cell mass and proliferation. The mutation also increases beta-cell resistance to hypoxia, and Ncx1(+/-) islets show a four to seven times higher rate of diabetes cure than Ncx1(+/+) islets when transplanted in diabetic animals. Thus, downregulation of the Na+/Ca2+ exchanger leads to various changes in beta-cell function that are opposite to the major abnormalities seen in diabetes. In addition, the beta-cell, which is an excitable cell, includes the mutually exclusive exon B in the alternative splicing region of NCX1, which confers a high sensitivity of its NCX splice variants (NCX1.3 & 1.7) to the inhibitory action of compounds like KB-R7943. This provides a unique model for the prevention and treatment of beta-cell dysfunction in diabetes and following islet transplantation.