Since deregulation of intracellular Ca²⁺ can lead to intracellular trypsin activation, and stromal interaction molecule-1 (STIM1) protein is the main regulator of Ca²⁺ homeostasis in pancreatic acinar cells, we explored the Ca²⁺ signaling in 37 STIM1 variants found in three pancreatitis patient cohorts. Extensive functional analysis of one particular variant, p.E152K, identified in three patients, provided a plausible link between dysregulated Ca²⁺ signaling within pancreatic acinar cells and chronic pancreatitis susceptibility. Specifically, p.E152K, located within the STIM1 EF-hand and sterile α-motif domain, increased the release of Ca²⁺ from the endoplasmic reticulum in patient-derived fibroblasts and transfected HEK293T cells. This event was mediated by altered STIM1–sarco/endoplasmic reticulum calcium transport ATPase (SERCA) conformational change and enhanced SERCA pump activity leading to increased store-operated Ca²⁺ entry (SOCE). In pancreatic AR42J cells expressing the p.E152K variant, Ca²⁺ signaling perturbations correlated with defects in trypsin activation and secretion, and increased cytotoxicity after cholecystokinin stimulation.

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由于细胞内 Ca ²⁺的失调可导致细胞内胰蛋白酶激活，而基质相互作用分子-1 (STIM1) 蛋白是胰腺腺泡细胞中 Ca ²⁺稳态的主要调节因子，我们探索了发现的 37 个 STIM1 变体中的 Ca ²⁺信号传导在三个胰腺炎患者队列中。在三名患者中发现的一种特定变体 p.E152K 的广泛功能分析提供了胰腺腺泡细胞内失调的 Ca ^{2+信号传导与慢性胰腺炎易感性之间的合理联系。}具体来说，p.E152K，位于 STIM1 EF 手和不育 α-基序结构域内，增加了 Ca ^2+的释放来自患者来源的成纤维细胞和转染的 HEK293T 细胞的内质网。这一事件是由改变的 STIM1-sarco/内质网钙转运 ATP 酶 (SERCA) 构象变化和增强的 SERCA 泵活性导致增加的储存操作的 Ca ²⁺进入 (SOCE) 介导的。在表达 p.E152K 变体的胰腺 AR42J 细胞中，Ca ²⁺信号传导扰动与胰蛋白酶活化和分泌缺陷相关，并在胆囊收缩素刺激后增加细胞毒性。

本文与论文的第一作者进行了相关的第一人称采访。