Hyperactivated DEG/ENaC channels cause neuronal death mediated by intracellular Ca²⁺ overload. Mammalian ASIC1a and C. elegans MEC-4(d) neurotoxic channels conduct both Na⁺ and Ca²⁺ raising the possibility that direct Ca²⁺ influx through these channels contributes to the intracellular Ca²⁺ overload. However, we showed that homologous C. elegans DEG/ENaC channel UNC-8(d) is not Ca²⁺ permeable yet it is neurotoxic, suggesting that Na⁺ influx is sufficient to induce cell death. Interestingly, UNC-8(d) shows small currents due to extracellular Ca²⁺ block in the Xenopus oocytes expression system. Thus, MEC-4(d) and UNC-8(d) differ both in current amplitude and Ca²⁺ permeability. Given that these two channels show a striking difference in toxicity, we asked what is the contribution of Na+ conductance versus Ca²⁺ permeability to cell death. To address this question we built a UNC-8/ MEC-4 chimeric channel that retains the calcium permeability of MEC-4 and characterized its properties in Xenopus oocytes. Our data support the hypothesis that for Ca²⁺ permeable DEG/ENaC channels, both Ca²⁺ permeability and Na⁺ conductance contribute to toxicity. However, for Ca²⁺ impermeable DEG/ENaCs (e.g., UNC-8) our evidence shows that constitutive Na⁺ conductance is sufficient to induce toxicity and that this effect is enhanced as current amplitude increases. Our work further refines the contribution of different channel properties to cellular toxicity induced by hyperactive DEG/ENaC channels.