Stanniocalcin 2 Is a Negative Modulator of Store-Operated Calcium Entry
Stanniocalcin 2 Is a Negative Modulator of Store-Operated Calcium Entry
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DOI：
10.1128/mcb.05140-11
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发表时间：
2011-07
影响因子：
5.3
通讯作者：
W. Zeiger;D. Ito;Carol Swetlik;M. Oh‐hora;M. Villereal;G. Thinakaran
中科院分区：
文献类型：
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作者：
W. Zeiger;D. Ito;Carol Swetlik;M. Oh‐hora;M. Villereal;G. Thinakaran
摘要细胞内钙稳态的调节在许多生理和病理过程中是必不可少的。斯钙素1是一种分泌型糖蛋白激素，最初在鱼类中被描述，是高钙血症期间鳃Ca 2+摄取的一种公认的内分泌调节剂。虽然存在两种哺乳动物斯钙素同源物（STC 1和STC 2），但它们的精确分子功能仍然未知。值得注意的是，STC 2是未折叠蛋白应答的促存活组分。在这里，我们证明了STC 2在调控钙库操纵的钙离子进入（SOCE）中的细胞内在作用。Stc2基因敲除小鼠培养的成纤维细胞在内质网（ER）Ca2+库耗竭后积累更高水平的胞质Ca2+，这特别是由于通过钙库操纵的Ca2+通道（SOC）的细胞外Ca2+内流增加。海马细胞系中STC 2表达的敲低也增强SOCE，并且STC 2的过表达减弱SOCE。此外，STC 2与ER Ca2+传感器STIM 1相互作用，其在ER储存耗尽后激活SOC。这些结果定义了STC 2作为SOCE负调节剂的新分子功能，并为哺乳动物STC 2调节Ca2+稳态提供了第一个直接证据。此外，我们的研究结果暗示通过STC 2表达的SOCE的调制作为未折叠蛋白反应的促生存措施之一。
ABSTRACT The regulation of cellular Ca2+ homeostasis is essential for innumerable physiological and pathological processes. Stanniocalcin 1, a secreted glycoprotein hormone originally described in fish, is a well-established endocrine regulator of gill Ca2+ uptake during hypercalcemia. While there are two mammalian Stanniocalcin homologs (STC1 and STC2), their precise molecular functions remain unknown. Notably, STC2 is a prosurvival component of the unfolded protein response. Here, we demonstrate a cell-intrinsic role for STC2 in the regulation of store-operated Ca2+ entry (SOCE). Fibroblasts cultured from Stc2 knockout mice accumulate higher levels of cytosolic Ca2+ following endoplasmic reticulum (ER) Ca2+ store depletion, specifically due to an increase in extracellular Ca2+ influx through store-operated Ca2+ channels (SOC). The knockdown of STC2 expression in a hippocampal cell line also potentiates SOCE, and the overexpression of STC2 attenuates SOCE. Moreover, STC2 interacts with the ER Ca2+ sensor STIM1, which activates SOCs following ER store depletion. These results define a novel molecular function for STC2 as a negative modulator of SOCE and provide the first direct evidence for the regulation of Ca2+ homeostasis by mammalian STC2. Furthermore, our findings implicate the modulation of SOCE through STC2 expression as one of the prosurvival measures of the unfolded protein response.