We describe here our current strategy for identifying and cloning proteins involved in the regulation of the epithelial sodium channel (ENaC). We have set up a complementation functional assay in the Xenopus laevis oocyte expression system. Using this assay, we have been able to identify a channel-activating protease (CAP-1) that can increase ENaC activity threefold. We propose a novel extracellular signal transduction pathway controlling ionic channels of the ENaC gene family that include genes involved in mechanotransduction (degenerins), in peptide-gated channels involved in neurotransmission (FaNaCh), in proton-gated channels involved in pH sensing (ASIC) or pain sensation (DRASIC).