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Nat Neurosci. 2004 Dec;7(12):1337-44. Epub 2004 Nov 7.

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

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Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, A232 Nelson Biological Laboratories, 604 Allison Road, Piscataway, New Jersey 08854, USA.


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 Ca(2+) and calpain activation. How exacerbated Na(+) channel activity elicits a toxic rise in cytoplasmic Ca(2+), however, has remained unclear. We tested the hypothesis that MEC-4(d)-induced membrane depolarization activates voltage-gated Ca(2+) channels (VGCCs) to initiate a toxic Ca(2+) influx, and ruled out a critical requirement for VGCCs. Instead, we found that MEC-4(d) itself conducts Ca(2+) both when heterologously expressed in Xenopus oocytes and in vivo in C. elegans touch neurons. Data generated using the Ca(2+) sensor cameleon suggest that an induced release of endoplasmic reticulum (ER) Ca(2+) is crucial for progression through necrosis. We propose a refined molecular model of necrosis initiation in which Ca(2+) influx through the MEC-4(d) channel activates Ca(2+)-induced Ca(2+) 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.

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