Stimulation of Ca²⁺-channel Orai1/STIM1 by serum-and glucocorticoid-inducible kinase 1 (SGK1)

Ca²⁺ signaling includes store-operated Ca²⁺ entry (SOCE) following depletion of endoplasmic reticulum (ER) Ca²⁺ stores. On store depletion, the ER Ca²⁺ sensor STIM1 activates Orai1, the pore-forming unit of Ca²⁺-release-activated Ca²⁺ (CRAC) channels. Here, we show that Orai1 is regulated by serum- and glucocorticoid-inducible kinase 1 (SGK1), a growth factor-regulated kinase. Membrane Orai1 protein abundance, I_CRAC, and SOCE in human embryonic kidney (HEK293) cells stably expressing Orai1 and transfected with STIM1 were each significantly enhanced by coexpression of constitutively active ^S422DSGK1 (by+81, +378, and +136%, respectively) but not by inactive ^K127NSGK1. Coexpression of the ubiquitin ligase Nedd4-2, an established negatively regulated SGK1 target, down-regulated SOCE (by -48%) and I_CRAC (by -60%), an effect reversed by expression of ^S422DSGK1 (by +175 and +173%, respectively). Orai1 protein abundance and SOCE were significantly lower in mast cells from SGK1-knockout (sgk1 ^-/-) mice (by -37% and -52%, respectively) than in mast cells from wild-type (sgk1^+/+) littermates. Activation of SOCE by sarcoplasmic/ endoplasmic reticulum Ca²⁺-ATPase-inhibitor thapsigargin (2 μM) stimulated migration, an effect significantly higher (by +306%) in ^S422DSGK1-expressing than in K127NSGK1-expressing HEK293 cells, and also significantly higher (by +108%) in sgk1^+/+ than in sgk1 ^-/- mast cells. SGK1 is thus a novel key player in the regulation of SOCE.