Store-operated calcium (Ca²⁺) entry is an important homeostatic mechanism in cells, whereby the release of Ca²⁺ from intracellular endoplasmic reticulum stores triggers the activation of a Ca²⁺ influx pathway. Mediated by Orai1, this Ca²⁺ influx has specific and essential roles in biological processes as diverse as lactation to immunity. Although pharmacological inhibitors of this Ca²⁺ influx mechanism have helped to define the role of store-operated Ca²⁺ entry in many cellular events, the lack of isoform specific modulators and activators of Orai1 has limited our full understanding of these processes. Here we report the identification and synthesis of an Orai1 activity enhancer that concurrently potentiated Orai1 Ca²⁺-dependent inactivation (CDI). This unique enhancer of Orai1 had only a modest effect on Orai3 with weak inhibitory effects at high concentrations in intact MCF-7 breast cancer cells. The Orai1 enhancer heightened vascular smooth muscle cell migration induced by platelet-derived growth factor and the unique store-operated Ca²⁺ entry pathway present in skeletal muscle cells. These studies show that IA65 is an exemplar for the translation and development of Orai isoform selective agents. The ability of IA65 to activate CDI demonstrates that agents can be developed that can enhance Orai1-mediated Ca²⁺ influx but avoid the cytotoxicity associated with sustained Orai1 activation. IA65 and/or future analogues with similar Orai1- and CDI-activating properties could function to fine-tune physiological processes important in specific disease states, such as cellular migration and immune cell function.

中文翻译：

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Orai1 Ca2 +通道的新型选择性药理增强剂揭示了Orai1在平滑肌和骨骼肌功能中的作用。

存储操作的钙（Ca ²⁺）进入是细胞中的重要稳态机制，因此从细胞内质网存储释放Ca ²⁺会触发Ca ^2+内流途径的激活。在Orai1的介导下，这种Ca ²⁺涌入在生物过程中具有特定而必不可少的作用，如免疫免疫。尽管此Ca ^2+内流机制的药理抑制剂已帮助确定了贮库操作的Ca ^2+的作用由于进入许多细胞事件，Orai1的同工型特异性调节剂和激活剂的缺乏限制了我们对这些过程的充分理解。在这里，我们报告鉴定和合成的Orai1活性增强剂，同时增强Orai1 Ca ²⁺依赖性失活（CDI）。在完整的MCF-7乳腺癌细胞中，Orai1的这种独特的增强剂仅对Orai3产生适度的抑制作用，而在高浓度下抑制作用较弱。Orai1增强剂增强了血小板衍生的生长因子和独特的存储操纵性Ca ²⁺诱导的血管平滑肌细胞迁移骨骼肌细胞中存在进入通道。这些研究表明，IA65是Orai亚型选择性试剂翻译和开发的典范。IA65激活CDI的能力表明，可以开发出可以增强Orai1介导的Ca ^2+内流但可以避免与持续的Orai1激活相关的细胞毒性的药物。IA65和/或具有类似Orai1-和CDI激活特性的未来类似物可用于微调在特定疾病状态下重要的生理过程，例如细胞迁移和免疫细胞功能。