Degenerin/epithelial Na(+) channels (DEG/ENaCs) are Na(+) channels that are blocked by the diuretic amiloride. In general, they are impermeable for Ca(2+) or have a very low permeability for Ca(2+). We describe here, however, that a DEG/ENaC from the cnidarian Hydra magnipapillata, the Hydra Na(+) channel (HyNaC), is highly permeable for Ca(2+) (P(Ca)/P(Na) = 3.8). HyNaC is directly gated by Hydra neuropeptides, and in Xenopus laevis oocytes expressing HyNaCs, RFamides elicit currents with biphasic kinetics, with a fast transient component and a slower sustained component. Although it was previously reported that the sustained component is unselective for monovalent cations, the selectivity of the transient component had remained unknown. Here, we show that the transient current component arises from secondary activation of the Ca(2+)-activated Cl(-) channel (CaCC) of Xenopus oocytes. Inhibiting the activation of the CaCC leads to a simple on-off response of peptide-activated currents with no apparent desensitization. In addition, we identify a conserved ring of negative charges at the outer entrance of the HyNaC pore that is crucial for the high Ca(2+) permeability, presumably by attracting divalent cations to the pore. At more positive membrane potentials, the binding of Ca(2+) to the ring of negative charges increasingly blocks HyNaC currents. Thus, HyNaC is the first member of the DEG/ENaC gene family with a high Ca(2+) permeability.