Ca2+ permeability and Na+ conductance in cellular toxicity caused by hyperactive DEG/ENaC channels

Cristina Matthewman, Tyne W. Miller-Fleming, David M. Miller, Laura Bianchi

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Hyperactivated DEG/ ENaC channels cause neuronal death mediated by intracellular Ca2+ overload. Mammalian ASIC1a channels and MEC-4 (d) neurotoxic channels in Caenorhabditis elegans both conduct Na+ and Ca2+, raising the possibility that direct Ca2+ influx through these channels contributes to intracellular Ca2+ overload. However, we showed that the 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 oocyte 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 wondered how Na+ conductance vs. Ca2+ permeability contributes to cell death. To address this question, we built an 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.

Original languageEnglish (US)
Pages (from-to)C920-C930
JournalAmerican Journal of Physiology - Cell Physiology
Volume311
Issue number6
DOIs
StatePublished - 2016

Keywords

  • Calcium permeability
  • DEG/ENaC channels
  • Neurotoxicity

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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