Hyperactivated DEG/ENaCs 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+ cation influx is sufficient to induce toxicity. Interestingly, UNC-8(d) shows small currents due to extracellular Ca2+ block. 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 in this channel family. To test the contribution of Na+ influx to cell death we replaced Na+ with impermeant cation choline and compared current amplitudes and cell death in oocytes expressing either MEC-4(d) or UNC-8(d). We found that cell death is strongly suppressed in UNC-8(d) expressing oocytes under these conditions, but not in oocytes expressing MEC-4(d). These results suggest that main contributor to cell death is Na+ for UNC-8(d) and Ca2+ for MEC-4(d). To test this hypothesis, we sought to confer Ca2+ permeability to the UNC-8 channel by swapping its second transmembrane domain (TM2), which houses the selectivity properties of these channels, with MEC-4. Indeed we found that the UNC-8(d)/MEC-4(TM2) chimeric protein is Ca2+ permeable. In addition, the elimination of extracellular Na+ from oocytes expressing UNC-8(d)/MEC-4(TM2) did not prevent cell death. Similar results were obtained with oocytes expressing MEC-4(d). These data support the idea that MEC-4(d) Ca2+ permeability is conferred by TM2 and that Ca2+ contributes to cell death in oocytes expressing Ca2+ permeable DEG/ENaCs. To conclude, our data show that both Na+ and Ca2+ conductance can kill cells that express hyperactive DEG/ENaC channels. However, for Ca2+ permeable DEG/ENaCs, Ca2+ appears to play a larger role.