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

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

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

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
Pages (from-to)1337-1344
Number of pages8
JournalNature Neuroscience
Volume7
Issue number12
DOIs
StatePublished - Dec 1 2004
Externally publishedYes

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Sodium Channels
Necrosis
Poisons
Caenorhabditis elegans
Calcium
Endoplasmic Reticulum
Molecular Models
Calpain
Touch
Xenopus
Oocytes
Ischemia
Neurons
Membranes

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Bianchi, L., Gerstbrein, B., Frøkjær-Jensen, C., Royal, D. C., Mukherjee, G., Royal, M. A., ... Driscoll, M. (2004). The neurotoxic MEC-4(d) DEG/ENaC sodium channel conducts calcium: Implications for necrosis initiation. Nature Neuroscience, 7(12), 1337-1344. https://doi.org/10.1038/nn1347

The neurotoxic MEC-4(d) DEG/ENaC sodium channel conducts calcium : Implications for necrosis initiation. / Bianchi, Laura; Gerstbrein, Beate; Frøkjær-Jensen, Christian; Royal, Dewey C.; Mukherjee, Gargi; Royal, Mary Anne; Xue, Jian; Schafer, William R.; Driscoll, Monica.

In: Nature Neuroscience, Vol. 7, No. 12, 01.12.2004, p. 1337-1344.

Research output: Contribution to journalArticle

Bianchi, L, Gerstbrein, B, Frøkjær-Jensen, C, Royal, DC, Mukherjee, G, Royal, MA, Xue, J, Schafer, WR & Driscoll, M 2004, 'The neurotoxic MEC-4(d) DEG/ENaC sodium channel conducts calcium: Implications for necrosis initiation', Nature Neuroscience, vol. 7, no. 12, pp. 1337-1344. https://doi.org/10.1038/nn1347
Bianchi L, Gerstbrein B, Frøkjær-Jensen C, Royal DC, Mukherjee G, Royal MA et al. The neurotoxic MEC-4(d) DEG/ENaC sodium channel conducts calcium: Implications for necrosis initiation. Nature Neuroscience. 2004 Dec 1;7(12):1337-1344. https://doi.org/10.1038/nn1347
Bianchi, Laura ; Gerstbrein, Beate ; Frøkjær-Jensen, Christian ; Royal, Dewey C. ; Mukherjee, Gargi ; Royal, Mary Anne ; Xue, Jian ; Schafer, William R. ; Driscoll, Monica. / The neurotoxic MEC-4(d) DEG/ENaC sodium channel conducts calcium : Implications for necrosis initiation. In: Nature Neuroscience. 2004 ; Vol. 7, No. 12. pp. 1337-1344.
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