Nature Neuroscience7, 1337 - 1344 (2004)
Published online: 7 November 2004; Corrected online: 14 November 2004 | doi:10.1038/nn1347
The neurotoxic MEC-4(d) DEG/ENaC sodium channel conducts calcium: implications for necrosis initiation
Laura Bianchi1, Beate Gerstbrein1, Christian Frøkjær-Jensen2, Dewey C Royal1, Gargi Mukherjee1, Mary Anne Royal1, Jian Xue1, William R Schafer2
& Monica Driscoll1
1
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.
2
Division of Biology, University of California, San Diego La Jolla, California 92093-0349, 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 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.
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