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XB-ART-2741
Nat Neurosci December 1, 2004; 7 (12): 1337-44.

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

Bianchi L , Gerstbrein B , FrĂžkjaer-Jensen C , Royal DC , Mukherjee G , Royal MA , Xue J , Schafer WR , Driscoll M .


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 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.

PubMed ID: 15543143
Article link: Nat Neurosci
Grant support: DA016445 NIDA NIH HHS , NS034435 NINDS NIH HHS , NS049511 NINDS NIH HHS , NS37955 NINDS NIH HHS , NSF00139 NINDS NIH HHS

Genes referenced: asic1



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