Gu Wenjia, Chen Jia-Hui, Zhang Yiyin, Wang Zhirong, Li Jia, Wang Sijia, Zhang Hanhan, Jiang Amin, Zhong Ziyi, Zhang Jiaxuan, Xu Ze, Liu Panpan, Xi Chao, Hou Tingting, Gill Donald L, Li Dong, Mu Yu, Wang Shi-Qiang, Tang Ai-Hui, Wang Youjun
Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing, China.
Department of Anatomy, School of Basic Medicine, Anhui Medical University, Hefei, Anhui, China.
Nat Commun. 2025 Apr 11;16(1):3472. doi: 10.1038/s41467-025-58705-6.
The Endoplasmic/sarcoplasmic reticulum (ER/SR) is central to calcium (Ca) signaling, yet current genetically encoded Ca indicators (GECIs) cannot detect elementary Ca release events from ER/SR, particularly in muscle cells. Here, we report NEMOer, a set of organellar GECIs, to efficiently capture ER Ca dynamics with increased sensitivity and responsiveness. NEMOer indicators exhibit dynamic ranges an order of magnitude larger than G-CEPIA1er, enabling 2.7-fold more sensitive detection of Ca transients in both non-excitable and excitable cells. The ratiometric version further allows super-resolution monitoring of local ER Ca homeostasis and dynamics. Notably, NEMOer-f enabled the inaugural detection of Ca blinks, elementary Ca releasing signals from the SR of cardiomyocytes, as well as in vivo spontaneous SR Ca releases in zebrafish. In summary, the highly dynamic NEMOer sensors expand the repertoire of organellar Ca sensors that allow real-time monitoring of intricate Ca dynamics and homeostasis in live cells with high spatiotemporal resolution.
内质网/肌浆网（ER/SR）是钙（Ca）信号传导的核心，但目前的基因编码钙指示剂（GECIs）无法检测到ER/SR的基本钙释放事件，尤其是在肌肉细胞中。在此，我们报告了NEMOer，这是一组细胞器GECIs，能够以更高的灵敏度和响应性有效捕获内质网钙动力学。NEMOer指示剂的动态范围比G-CEPIA1er大一个数量级，在非兴奋性和兴奋性细胞中对钙瞬变的检测灵敏度提高了2.7倍。比率型版本还允许对局部内质网钙稳态和动力学进行超分辨率监测。值得注意的是，NEMOer-f首次检测到了钙闪烁，即心肌细胞肌浆网的基本钙释放信号，以及斑马鱼体内自发的肌浆网钙释放。总之，高度动态的NEMOer传感器扩展了细胞器钙传感器的种类，能够以高时空分辨率实时监测活细胞中复杂的钙动力学和稳态。
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