Brain Science Institute, RIKEN, Wako, Saitama, Japan.
Cell Calcium. 2010 Jan;47(1):1-10. doi: 10.1016/j.ceca.2009.10.004. Epub 2009 Nov 27.
Store-operated calcium entry (SOCE) or calcium release-activated calcium current (I(CRAC)) is a critical pathway to replenish intracellular calcium stores, and plays indispensable roles in cellular functions such as antigen-induced T lymphocyte activation. Despite the importance of I(CRAC) in cellular functions, lack of potent and specific inhibitor has limited the approaches to the function of I(CRAC) in native cells. 2-Aminoethyl diphenylborinate (2-APB) is a widely used SOCE/I(CRAC) inhibitor, while its effect is rather unspecific. In the attempt to develop more potent and selective compounds here we identified two structurally isomeric 2-APB analogues that are 100-fold more potent than 2-APB itself. One of the 2-APB analogues activates and inhibits endogenous SOCE depending on the concentration while the other only inhibits it. The 2-APB analogue inhibits store depletion-mediated STIM1 clustering as well as heterologously expressed CRAC current. Together with the observation that, unlike 2-APB, the analogue compounds failed to activate CRACM3/Orai3 current in the absence of STIM, our results suggest that inhibition and activation of SOCE/I(CRAC) by the 2-APB analogues is mediated by STIM.
钙库操纵性钙内流（SOCE）或钙释放激活钙电流（I（CRAC））是补充细胞内钙库的关键途径，在细胞功能中发挥着不可或缺的作用，如抗原诱导的 T 淋巴细胞激活。尽管 I（CRAC）在细胞功能中的重要性，但缺乏有效且特异的抑制剂限制了对天然细胞中 I（CRAC）功能的研究。2-氨基乙基二苯硼酸盐（2-APB）是一种广泛使用的 SOCE/I（CRAC）抑制剂，但作用相当不特异。在尝试开发更有效和选择性的化合物时，我们鉴定了两种结构异构的 2-APB 类似物，它们比 2-APB 本身强 100 倍。2-APB 类似物之一可根据浓度激活和抑制内源性 SOCE，而另一种仅抑制它。该 2-APB 类似物抑制了由钙库耗竭介导的 STIM1 聚集以及异源表达的 CRAC 电流。与观察到的 2-APB 不同，类似物化合物在没有 STIM 的情况下未能激活 CRACM3/Orai3 电流，我们的结果表明，2-APB 类似物对 SOCE/I（CRAC）的抑制和激活是由 STIM 介导的。
