Coping with the calcium overload caused by cell injury: ER to the rescue.
Coping with the calcium overload caused by cell injury: ER to the rescue.
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应对细胞损伤引起的钙超载：ER的救星。
DOI：
10.15698/cst2021.05.249
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发表时间：
2021-04-16
期刊：
影响因子：
6.4
通讯作者：
Jaiswal JK
中科院分区：
文献类型：
--
作者：
Chandra G;Mázala DAG;Jaiswal JK
细胞将其细胞溶质钙（Ca 2+）维持在纳摩尔范围内，并使用Ca 2+的受控增加用于细胞内信号传导。当细胞外Ca 2+在毫摩尔范围内时，跨质膜（PM）存在陡峭的Ca 2+梯度。因此，损伤PM的损伤导致胞质Ca 2+过载，这有助于激活PM修复（PMR）反应。然而，为了生存，细胞必须科普Ca 2+过载。在最近的一项研究中（Chandra等人，J Cell Biol，doi：10.1083/jcb.202006035），我们已经检查了细胞如何科普损伤诱导的胞质Ca 2+过载。通过监测胞浆和内质网（ER）中的Ca 2+动态，我们发现PM损伤触发的胞浆Ca 2+增加被ER吸收。ER Ca 2+摄取的药理学抑制干扰了这一过程，并损害了受损细胞的修复能力。来自肌营养不良症患者和小鼠模型的肌细胞显示，缺乏Anoctamin 5（ANO 5）/跨膜蛋白16 E（TMEM 16 E）（一种ER驻留的推定的Ca 2+激活的氯离子通道（CaCC）），在应对胞质Ca 2+过载方面很差。CaCC的药理学抑制和ANO 5的缺乏都阻止Ca 2+摄取到ER中。这些研究确定了ER在隔离损伤触发的ER中胞质Ca 2+增加中Cl-摄取的要求。此外，这些研究表明，ER有助于受损细胞科普PMR期间的Ca 2+过载，缺乏这种过载会导致ANO 5蛋白突变导致肌营养不良。
Cells maintain their cytosolic calcium (Ca2+) in nanomolar range and use controlled increase in Ca2+ for intracellular signaling. With the extracellular Ca2+ in the millimolar range, there is a steep Ca2+ gradient across the plasma membrane (PM). Thus, injury that damages PM, leads to a cytosolic Ca2+ overload, which helps activate PM repair (PMR) response. However, in order to survive, the cells must cope with the Ca2+ overload. In a recent study (Chandra et al. J Cell Biol, doi: 10.1083/jcb.202006035) we have examined how cells cope with injury-induced cytosolic Ca2+ overload. By monitoring Ca2+ dynamics in the cytosol and endoplasmic reticulum (ER), we found that PM injury-triggered increase in cytosolic Ca2+ is taken up by the ER. Pharmacological inhibition of ER Ca2+ uptake interferes with this process and compromises the repair ability of the injured cells. Muscle cells from patients and mouse model for the muscular dystrophy showed that lack of Anoctamin 5 (ANO5)/Transmembrane protein 16E (TMEM16E), an ER-resident putative Ca2+-activated chloride channel (CaCC), are poor at coping with cytosolic Ca2+ overload. Pharmacological inhibition of CaCC and lack of ANO5, both prevent Ca2+ uptake into ER. These studies identify a requirement of Cl- uptake by the ER in sequestering injury-triggered cytosolic Ca2+ increase in the ER. Further, these studies show that ER helps injured cells cope with Ca2+ overload during PMR, lack of which contributes to muscular dystrophy due to mutations in the ANO5 protein.