Gordon Research Conference on Ca2+ Signalling 2017 Editorial.
Gordon Research Conference on Ca2+ Signalling 2017 Editorial.
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戈登 Ca2 信号研究会议 2017 年社论。
DOI：
10.1113/jp276271
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Glitsch MD
中科院分区：
文献类型：
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作者：
Glitsch MD
细胞内 Ca2+ 浓度的变化影响许多生理反应，而 Ca2+ 信号传导失调与各种人类疾病密切相关。异常 Ca2+ 信号如何促进疾病进展的一个突出例子是急性胰腺炎，这是一种破坏性的疾病，目前尚无有效的治疗方法。虽然人们对不同类型的胰腺细胞如何受到这种疾病的影响以及如何导致这种疾病了解很多，但不同的细胞如何相互沟通尚不清楚。 Ole Petersen 及其同事通过一系列巧妙的实验发现了胰腺星状 (PS) 细胞意想不到的重要新作用。 PS 细胞被认为介导慢性炎症反应，并且在生理条件下，对缓激肽做出反应，但对丝氨酸蛋白酶、胰蛋白酶或膜去极化不做出反应，以增加细胞内 Ca2+ 浓度。然而，当胰小叶暴露于乙醇和棕榈油酸的混合物（以在体外模拟急性胰腺炎）或来自体内诱导急性胰腺炎的小鼠时，这种情况会发生巨大变化。 PS 细胞现在对缓激肽的反应较弱，但对胰蛋白酶的反应强烈，这可能有助于促进急性胰腺炎进展的正反馈循环（Gryshchenko 等人，2018 年；Hegyi，2018 年）。在细胞毒性 T 淋巴细胞 (CTL) 和自然杀伤 (NK) 细胞中发现了细胞内 Ca2+ 升高如何促进疾病进展的一个有趣的转折 (Zhou et al. 2018)。这些免疫细胞对于消除癌细胞至关重要，并且在远低于生理水平的细胞外 Ca2+ 浓度下发挥最佳作用；在这些细胞外 Ca2+ 水平上激活 Ca2+ 流入途径会损害 CTL 对癌细胞的穿孔素依赖性杀伤，从而促进癌症进展。 CTL 中主要 Ca2+ 流入途径（存储操纵的 Orai1 通道）的下调，导致溶解颗粒释放增加和随后的癌细胞死亡。从治疗的角度来看，这些发现可能非常重要。库操作的 Orai1 通道抑制剂会减少生理外部 Ca2+ 中 CTL 中的 Ca2+ 流入，因此应该会增加 CTL 依赖性杀伤癌细胞。免疫细胞还参与针对病原体入侵和定植的防御机制。中性粒细胞作为第一道防线发挥着特别重要的作用，许多功能都依赖于功能性 STIM 蛋白 (Saul & Demaurex, 2018)。 STIM1 和 2 是跨内质网 (ER) 膜的 Ca2+ 传感蛋白，是钙池操纵通道门控所必需的。内质网失去 Ca2+ 后，STIM 蛋白寡聚化，然后迁移到质膜附近的内质网区域，在那里它们结合并门控 Orai 通道，从而启动钙池操纵的 Ca2+ 进入。 STIM 蛋白在中性粒细胞功能中发挥的确切作用尚不完全清楚，关于它们对趋化性影响的相互矛盾的报告需要解决，但正在出现的是，这两种亚型单独和协同地促进不同的过程。
Changes in intracellular Ca2+ concentration influence numerous physiological responses, and dysregulated Ca2+ signalling is tightly linked to various human diseases. One prominent example of how aberrant Ca2+ signalling promotes disease progression is acute pancreatitis, a devastating condition for which there is currently no effective therapy. Whilst much is known about how different pancreatic cell types are affected by and contribute to this disease, how the different cells communicate with one another is unclear. An unexpected and important new role for pancreatic stellate (PS) cells has been uncovered in a series of elegant experiments by Ole Petersen and colleagues. PS cells are thought to mediate chronic inflammatory responses and, under physiological conditions, respond to bradykinin but not to the serine protease trypsin or membrane depolarisation to increase intracellular Ca2+ concentration. However, this changes dramatically when pancreatic lobules are either exposed to a mixture of ethanol and palmitoleic acid (to mimic acute pancreatitis in vitro) or are derived from mice in which acute pancreatitis has been induced in vivo. PS cells are now less responsive to bradykinin but respond strongly to trypsin, and this is likely to contribute to a positive feedback cycle that promotes acute pancreatitis progression (Gryshchenko et al. 2018; Hegyi, 2018). An interesting twist on how an intracellular Ca2+ rise can promote disease progression has been identified in cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells (Zhou et al. 2018). These immune cells are crucial for elimination of cancer cells and operate best at extracellular Ca2+ concentrations that are well below physiological levels; activation of Ca2+ influx pathways at these extracellular Ca2+ levels impairs the perforin-dependent killing of cancer cells by CTLs, thus contributing to cancer progression. Downregulation of the major Ca2+ influx pathway in CTLs, store-operated Orai1 channels, results in increased lytic granule release and subsequent cancer cell death. From a therapeutic perspective, these findings could be potentially very important. A store-operated Orai1 channel inhibitor would reduce Ca2+ influx in CTLs at physiological external Ca2+, and therefore should increase the CTL-dependent killing of cancer cells.Immune cells are also involved in defence mechanisms against pathogen invasion and colonisation. Neutrophils play a particularly important role as a first line of defence, and numerous functions are dependent on functional STIM proteins (Saul & Demaurex, 2018). STIM1 and 2 are Ca2+ sensing proteins that span the endoplasmic reticulum (ER) membrane and are required for the gating of store-operated channels. Following the loss of Ca2+ from the ER, STIM proteins oligomerise and then migrate to regions of the ER adjacent to the plasma membrane, where they bind to and gate Orai channels, thereby initiating store-operated Ca2+ entry. The exact roles that STIM proteins play in neutrophil function are not entirely clear, and conflicting reports as to their impact on chemotaxis need resolving, but what is emerging is that the two isoforms contribute to distinct processes, both individually and synergistically.