Photopharmacological modulation of native CRAC channels using azoboronate photoswitches.
Photopharmacological modulation of native CRAC channels using azoboronate photoswitches.
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DOI：
10.1073/pnas.2118160119
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发表时间：
2022-03-29
影响因子：
11.1
通讯作者：
Palty, Raz
中科院分区：
文献类型：
--
作者：
Udasin, Ronald;Sil, Anwesha;Zomot, Elia;Cohen, Hadas Achildiev;Haj, Jozafina;Engelmayer, Nurit;Lev, Shaya;Binshtok, Alexander M.;Shaked, Yuval;Kienzler, Michael A.;Palty, Raz
钙释放激活的钙（CRAC）通道在细胞信号传导、转录和迁移的调节中起关键作用。在这里，我们描述的设计，化学合成和表征的光开关通道抑制剂，可以打开和关闭取决于所使用的光的波长。我们使用这些化合物来诱导人类免疫细胞中通道活性和下游基因表达的光依赖性调节。我们进一步扩展了化合物的用途，以控制癌细胞在靶组织中的接种和调节小鼠体内对有害刺激的反应。通过钙释放激活的钙通道（CRAC）的钙库操作的钙进入破坏细胞内钙库，并在细胞钙信号转导中起关键作用。CRAC通道通过内质网（ER）钙传感器STIM蛋白和质膜（PM）奥赖通道之间的严格调节的相互作用激活。我们目前对STIM-Orai依赖性钙信号在生理相关条件下的作用的理解仍然有限，部分原因是缺乏用于直接操纵内源性CRAC通道的时空精确方法。在这里，我们报告的偶氮硼酸光操作的CRAC通道抑制剂（LOCI），允许使用紫外线（UV）和可见光的天然CRAC通道的功能的动态和完全可逆的远程调制的合成和表征。我们证明使用LOCI-1调节T淋巴细胞中的基因表达，转移部位的癌细胞接种和疼痛相关行为。
Calcium release–activated calcium (CRAC) channels play key roles in the regulation of cellular signaling, transcription, and migration. Here, we describe the design, chemical synthesis, and characterization of photoswitchable channel inhibitors that can be switched on and off depending on the wavelength of light used. We use the compounds to induce light-dependent modulation of channel activity and downstream gene expression in human immune cells. We further expand the usage of the compounds to control seeding of cancer cells in target tissue and regulation of response to noxious stimuli in vivo in mice. Store-operated calcium entry through calcium release–activated calcium (CRAC) channels replenishes intracellular calcium stores and plays a critical role in cellular calcium signaling. CRAC channels are activated by tightly regulated interaction between the endoplasmic reticulum (ER) calcium sensor STIM proteins and plasma membrane (PM) Orai channels. Our current understanding of the role of STIM–Orai-dependent calcium signals under physiologically relevant conditions remains limited in part due to a lack of spatiotemporally precise methods for direct manipulation of endogenous CRAC channels. Here, we report the synthesis and characterization of azoboronate light-operated CRAC channel inhibitors (LOCIs) that allow for a dynamic and fully reversible remote modulation of the function of native CRAC channels using ultraviolet (UV) and visible light. We demonstrate the use of LOCI-1 to modulate gene expression in T lymphocytes, cancer cell seeding at metastatic sites, and pain-related behavior.
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影响因子：
64.8
作者：
HOTH, M;PENNER, R
通讯作者：
PENNER, R
影响因子：
5.3
作者：
Dou, Yannong;Xia, Jingsheng;Hu, Huijuan
通讯作者：
Hu, Huijuan
影响因子：
7.4
作者：
Xia J;Dou Y;Mei Y;Munoz FM;Gao R;Gao X;Li D;Osei-Owusu P;Schiffenhaus J;Bekker A;Tao YX;Hu H
通讯作者：
Hu H
影响因子：
16.6
作者：
Ishii T;Sato K;Kakumoto T;Miura S;Touhara K;Takeuchi S;Nakata T
通讯作者：
Nakata T
影响因子：
2.9
作者：
Alamri, Abdulhakeem;Bron, Romke;Ivanusic, Jason J.
通讯作者：
Ivanusic, Jason J.