Ke Yuepeng, Gannaban Ritchel, Liu Junchen, Zhou Yubin
Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas, United States.
Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center, Houston, Texas, United States.
Am J Physiol Cell Physiol. 2025 Jan 1;328(1):C107-C114. doi: 10.1152/ajpcell.00634.2024. Epub 2024 Dec 2.
Store-operated calcium (Ca) entry (SOCE) represents a major route of Ca permeation across the plasma membrane (PM) in nonexcitable cells, which plays an indispensable role in maintaining intracellular Ca homeostasis. This process is orchestrated through the dynamic coupling between the endoplasmic reticulum (ER)-localized Ca sensor stromal interaction molecule 1 (STIM1) and the PM-resident ORAI1 channel. Upon depletion of ER Ca stores, STIM1 undergoes conformational rearrangements and oligomerization, leading to the translocation of activated STIM1 toward the PM. This movement is facilitated by the physical interactions between positively charged cytosolic domains within STIM1 and negatively charged phospholipids embedded in the PM, ultimately enabling its binding to and activation of the PM-embedded ORAI1 channel. In this mini-review, we provide an overview of STIM1-mediated Ca signaling at ER-PM contact sites, highlighting the regulatory roles of phospholipids in the inner leaflet and sphingolipids in the outer leaflet of the PM. We also discuss the development of molecular tools that enable real-time visualization and manipulation of membrane contact sites (MCSs) at ER-PM junctions. Finally, we highlight recent progress in developing targeted therapies for human diseases linked to STIM1 mutations and dysregulated Ca signaling at ER-PM MCSs.
钙库操纵性钙（Ca）内流（SOCE）是钙在非兴奋性细胞中穿过质膜（PM）的主要途径，在维持细胞内钙稳态中发挥着不可或缺的作用。这一过程是通过内质网（ER）定位的钙传感器基质相互作用分子1（STIM1）与质膜驻留的ORAI1通道之间的动态偶联来协调的。内质网钙库耗尽后，STIM1发生构象重排和寡聚化，导致活化的STIM1向质膜移位。STIM1内带正电荷的胞质结构域与质膜中嵌入的带负电荷的磷脂之间的物理相互作用促进了这种移动，最终使其能够与质膜中嵌入的ORAI1通道结合并激活该通道。在这篇小型综述中，我们概述了内质网-质膜接触位点处STIM1介导的钙信号传导，强调了质膜内小叶中的磷脂和外小叶中的鞘脂的调节作用。我们还讨论了能够实时可视化和操纵内质网-质膜连接处膜接触位点（MCSs）的分子工具的开发。最后，我们强调了在开发针对与STIM1突变和内质网-质膜MCSs处钙信号失调相关的人类疾病的靶向治疗方面的最新进展。
