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

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.