Calcium homoeostasis modulator 1 (CALHM1) reduces the calcium content of the endoplasmic reticulum (ER) and triggers ER stress
Calcium homoeostasis modulator 1 (CALHM1) reduces the calcium content of the endoplasmic reticulum (ER) and triggers ER stress
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DOI：
10.1042/bj20110479
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发表时间：
2011-08-01
影响因子：
4.1
通讯作者：
Garcia-Sancho, Javier
中科院分区：
文献类型：
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作者：
Gallego-Sandin, Sonia;Teresa Alonso, Maria;Garcia-Sancho, Javier
CALHM 1（钙稳态调节剂1）是一种与NMDA（N-甲基-D-天冬氨酸）受体通道相似的膜蛋白，其定位于神经元的质膜和内质网（ER）中，已显示产生质膜Ca 2+电导，并已提出影响阿尔茨海默病风险。在本研究中，我们研究了CALHM 1对HEK-293 T [HEK（人胚肾）-293细胞表达SV 40（猿猴病毒40）的大T抗原]细胞内Ca 2+处理的影响，通过使用靶向水母发光蛋白选择性监测细胞器的Ca 2+转运。我们发现，CALHM 1增加Ca 2+从ER泄漏，更重要的是，通过降低SERCA（肌质/内质网Ca 2 +-ATP酶）的转运能力和Ca 2+亲和力来减少ER Ca 2+摄取。结果，ER的Ca 2+含量急剧降低。ER的Ca 2+含量的这种降低引发了UPR（未折叠蛋白反应），诱导了几种ER应激标志物，如CHOP [C/EBP（CCAAT/增强子结合蛋白）-同源蛋白]、ERdj 4、GRP 78（78 kDa的葡萄糖调节蛋白）和XBP 1（X盒结合蛋白1）。因此，CALHM 1可能在神经退行性疾病的发病机制中提供Ca 2+稳态破坏、ER应激和细胞损伤之间的相关联系
CALHM1 (calcium homoeostasis modulator 1), a membrane protein with similarity to NMDA (N-methyl-D-aspartate) receptor channels that localizes in the plasma membrane and the ER (endoplasmic reticulum) of neurons, has been shown to generate a plasma-membrane Ca2+ conductance and has been proposed to influence Alzheimer's disease risk. In the present study we have investigated the effects of CALHM1 on intracellular Ca2+ handling in HEK-293T [HEK (human embryonic kidney)-293 cells expressing the large T-antigen of SV40 (simian virus 40)] cells by using targeted aequorins for selective monitorization of Ca2+ transport by organelles. We find that CALHM1 increases Ca2+ leak from the ER and, more importantly, reduces ER Ca2+ uptake by decreasing both the transport capacity and the Ca2+ affinity of SERCA (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase). As a result, the Ca2+ content of the ER is drastically decreased. This reduction in the Ca2+ content of the ER triggered the UPR (unfolded protein response) with induction of several ER stress markers, such as CHOP [C/EBP (CCAAT/enhancer-binding protein)-homologous protein], ERdj4, GRP78 (glucose-regulated protein of 78 kDa) and XBP1 (X-box-binding protein 1). Thus CALHM1 might provide a relevant link between Ca2+ homoeostasis disruption, ER stress and cell damage in the pathogenesis of neurodegenerative diseases