The recently published crystal structure of the acid sensing ion channel (ASIC1) suggests that the related epithelial sodium channel (ENaC) is probably a heterotrimeric channel. ENaC has three well characterized subunits called a, ß, and g. In humans an additional d-subunit (dhENaC) exists and may be co-expressed with ß- and ghENaC. So far little is known about the physiological role and function of this additional subunit. Therefore, we compared the functional properties of aßg- and dßghENaC expressed in Xeonpus laevis oocytes. The amiloride-sensitive whole-cell current (DI_ami) was ~11-fold larger in oocytes expressing dßghENaC compared to control oocytes expressing aßghENaC. The single-channel Na⁺-conductance of dßghENaC is known to be larger than that of aßghENaC (~12 pS vs. ~5 pS). However, this cannot explain the ~11-fold larger DI_ami in oocytes expressing dßgENaC. Using a FLAG-tagged ßhENaC construct we demonstrated that an increased channel expression at the cell surface also is not the cause for the increased DI_ami. To investigate whether an increased open probability (Po) of dßghENaC contributes to the increased DI_ami, we used the S520C mutant of ßhENaC which can be converted to a channel with a Po of nearly one by exposure to a sulfhydryl reagent. We found that the average PO of dßghENaC is significantly higher than that of aßghENaC. Moreover, Na⁺ feedback inhibition and the stimulatory effect of chymotrypsin on DI_ami were reduced in oocytes expressing dßghENaC compared to the effects in oocytes expressing aßghENaC. Finally, we demonstrated that a short inhibitory 13-mer peptide (LRGTLPHPLQRLR) corresponding to a region of the extracellular loop of human aENaC inhibited DI_ami in oocytes expressing aßgENaC but not in those expressing dßgENaC. We conclude that in humans the differential expression of dßghENaC versus aßghENaC may provide an additional mechanism to regulate ENaC activity.