The degenerin (DEG)/ epithelial sodium channel (ENaC) gene family represents a class of sodium selective ion channels found in nearly all multicellular animals (metazoa). It was shown recently that FMRFamide, a common neuropeptide in invertebrates, is modulating two subgroups of the DEG/ENaC family. It activates FMRF activated Na+ channels (FaNaCs), and modulates the currents of acid sensing ion channels (ASICs). We have cloned new DEG/ENaC subunits from the freshwater polyp Hydra magnipapillata (HyNaCs), which are functional when expressed in Xenopus oocytes. Large currents can be elicited by two FMRF-related peptides that had been isolated from Hydra. A phylogenetic analysis shows that HyNaCs are close relatives of ASICs and BLINaCs/INaCs, a subgroup of the DEG/ENaC superfamily with an unknown ligand, mainly expressed in the intestine of vertebrates. Cnidarians, to which Hydras belong, are the most basal metazoans, suggesting that HyNaCs resemble the ancestral DEG/ENaC ion channel. Our findings suggest that peptides are ancient ligands for this family of ion channels and are probably playing a more general role in modulating them.