Department of Physiology, University of Tübingen, Gmelinstr. 5, D-72076 Tübingen, Germany.
Cell Calcium. 2012 Nov;52(5):347-54. doi: 10.1016/j.ceca.2012.05.005. Epub 2012 Jun 7.
STIM and Orai isoforms orchestrate store operated Ca2+ entry (SOCE) and thus cytosolic Ca2+ fluctuations following stimulation by hormones, growth factors and further mediators. Orai1 is a target of Nedd4-2, an ubiquitin ligase preparing several plasma membrane proteins for degradation. Phosphorylation of Nedd4-2 by the serum and glucocorticoid inducible kinase SGK1 leads to the binding of Nedd4-2 to the protein 14-3-3 thus preventing its interaction with Orai1. Nedd4-2 is activated by the energy sensing AMP activated kinase AMPK. Thus, SGK1 disrupts and AMPK fosters degradation of Orai1. New synthesis of both, Orai1 and STIM1, is stimulated by the transcription factor NF-κB (nuclear factor kappa B), which binds to the respective promoter regions of the genes encoding STIM1 and Orai1. SGK1 upregulates and AMPK presumably downregulates NF-κB and thus de novo synthesis of Orai1 and STIM1 proteins. The regulation by SGK1 links SOCE to the signaling of a wide variety of hormones and growth factors, the AMPK dependent regulation of Orai1 and STIM1 may serve to limit inadequate activation of SOCE following energy depletion, which is otherwise expected to activate SOCE by depletion of intracellular Ca2+ stores due to impairment of the ATP consuming sarco/endoplasmatic reticulum Ca2+ ATPase SERCA.
STIM 和 Orai 同工型协调储存操作的钙内流（SOCE），从而在激素、生长因子和其他介质刺激后引起细胞浆钙波动。Orai1 是 Nedd4-2 的靶标，Nedd4-2 是一种泛素连接酶，可使几种质膜蛋白降解。血清和糖皮质激素诱导激酶 SGK1 使 Nedd4-2 磷酸化，导致 Nedd4-2 与蛋白 14-3-3 结合，从而阻止其与 Orai1 相互作用。Nedd4-2 被能量感应 AMP 激活的蛋白激酶 AMPK 激活。因此，SGK1 破坏了 AMPK 促进 Orai1 的降解。转录因子 NF-κB（核因子 kappa B）刺激 Orai1 和 STIM1 的新合成，NF-κB 结合编码 STIM1 和 Orai1 的基因的相应启动子区域。SGK1 上调 AMPK 可能下调 NF-κB，从而新合成 Orai1 和 STIM1 蛋白。SGK1 的调节将 SOCE 与各种激素和生长因子的信号联系起来，AMPK 对 Orai1 和 STIM1 的调节可能有助于限制能量耗竭后 SOCE 的过度激活，否则由于 ATP 消耗的肌浆/内质网 Ca2+ATP 酶 SERCA 的损伤，细胞内 Ca2+ 储存的耗竭预计会激活 SOCE。
