The energy sensing enzyme AMP-activated protein kinase (AMPK) counteracts energy depletion by stimulation of energy production and limitation of energy utilisation. Activation of the AMPK thus fosters cell survival during energy depletion. AMPK is in part effective through activation of the ubiquitin ligase Nedd4-2 (neuronal precursor cells expressed developmentally downregulated). In theory, energy depletion should compromize the function of sarcoendoplasmatic reticulum Ca²⁺ ATPase SERCA, leading to depletion of intracellular Ca²⁺ stores and triggering of potentially detrimental store operated Ca²⁺ entry (SOCE), which is accomplished by activation of the pore forming Ca²⁺ channel subunit Orai. The present study thus explored, whether AMPK influences Orai1 protein abundance and SOCE. To this end fibroblasts were isolated from AMPKa1-deficient mice (ampk^-/-) and their wild type littermates (ampk^+/+). According to immunohistochemistry and confocal microscopy, Orai1 protein abundance was significantly more abundant, and according to Fluo2 fluorescence SOCE significantly higher in ampk^-/- fibroblasts than in ampk^+/+ fibroblasts. Additional experiments were performed in Orai1 expressing HEK cells to elucidate the effect of Nedd4-2 on Orai protein abundance and function. According to Western blotting, immunohistochemistry and Fluo-2 fluorescence, respectively overexpression of Nedd4-2, significantly downregulated Orai1 protein abundance and SOCE. In conclusion, AMPK is a powerful negative regulator of SOCE, an effect possibly in part due to Nedd4-2 dependent stimulation of Orai1 ubiquitination.