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

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.