The neurotoxic MEC-4(d) DEG/ENaC sodium channel conducts calcium: Implications for necrosis initiation

Laura Bianchi, Beate Gerstbrein, Christian Froekjaer Jensen, Dewey C. Royal, Gargi Mukherjee, Mary Anne Royal, Jian Xue, William R. Schafer, Monica Driscoll*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

106 Scopus citations


Hyperactivation of the Caenorhabditis elegans MEC-4 Na+ channel of the DEG/ENaC superfamily (MEC-4(d)) induces neuronal necrosis through an increase in intracellular Ca2+ and calpain activation. How exacerbated Na+ channel activity elicits a toxic rise in cytoplasmic Ca2+, however, has remained unclear. We tested the hypothesis that MEC-4(d)-induced membrane depolarization activates voltage-gated Ca2+ channels (VGCCs) to initiate a toxic Ca2+ influx, and ruled out a critical requirement for VGCCs. Instead, we found that MEC-4(d) itself conducts Ca2+ both when heterologously expressed in Xenopus oocytes and in vivo in C. elegans touch neurons. Data generated using the Ca2+ sensor cameleon suggest that an induced release of endoplasmic reticulum (ER) Ca2+ is crucial for progression through necrosis. We propose a refined molecular model of necrosis initiation in which Ca2+ influx through the MEC-4(d) channel activates Ca2+-induced Ca2+ release from the ER to promote neuronal death, a mechanism that may apply to neurotoxicity associated with activation of the ASIC1a channel in mammalian ischemia.

Original languageEnglish (US)
Pages (from-to)1337-1344
Number of pages8
JournalNature Neuroscience
Issue number12
StatePublished - Dec 1 2004

ASJC Scopus subject areas

  • Neuroscience(all)


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