Regulation of Orai1/STIM1 by the kinases SGK1 and AMPK.

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.