Objective. The epithelial sodium channel (ENaC) is probably a heterotrimer with three well characterized subunits (abg). In humans an additional d-subunit exists and may replace the a-subunit in certain tissues. This possibly alters channel function and regulation, e.g. by kinases. Rat abg-ENaC, heterologously expressed in Xenopus laevis oocytes, can be activated in outside-out patches by recombinant SGK1 (serum and glucocortocoide inducible kinase type 1). This stimulatory effect is critically dependent on serine residue S621 in the C-terminus of the a-subunit (Diakov & Korbmacher, J Biol Chem 2004, 279: 38134). In the present study we investigated the effect of SGK1 on human abg- ENaC and dbg-ENaC. Methods. Patch clamp measurements were performed in outside-out macro patches excised from human abg-ENaC or dbg-ENaC expressing Xenopus laevis oocytes. ENaC activity was determined by measuring the amiloride- sensitive current (DI_ami). Pipette solution contained either active or heat- inactivated recombinant SGK1. Results. Within ~12 min after patch excision SGK1 increased DI_ami to 254±18% (n=6; ± SEM; p<0.001) of its starting value in patches from oocytes expressing abg-ENaC. In contrast, SGK1 failed to stimulate DI_ami in patches excised from oocytes expressing dbg-ENaC (n=5). An alanine to serine exchange of the conserved S594 residue in human a-ENaC, corresponding to S621 in rat a-ENaC, abolished the stimulatory effect of SGK1 on abg-ENaC (n=8). Conclusions. We demonstrate that SGK1 can stimulate human abg- ENaC. This stimulation requires a conserved amino acid motif in the C-terminus of the channel's a-subunit. In contrast, this motif is absent in the d-subunit which is likely to explain the lack of stimulation of dbg-ENaC by SGK1. The different responsiveness of abg-ENaC and dbg-ENaC to SGK1 may contribute to tissue specific channel regulation depending on its subunit composition.