Here, we report the presence of two splice variants of the human epithelial sodium channel alpha subunit (h alpha ENaC) containing Alu cassette, namely h alpha ENaC+22 and h alpha ENaC+Alu, in various tissues. Functional expression of these splice variants with hENaC beta and gamma subunits produced loss-of-channel activity in the Xenopus oocyte expression system. Interestingly, coexpression of h alpha ENaC+22 or h alpha ENaC+Alu, respectively, with wild type hENaC alpha, beta, and gamma subunits enhanced the expression of amiloride-sensitive current in oocytes. The presence of Alu sequences in the 3'-untranslated region of h gamma ENaC was also identified.