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 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.
Bianchi
Laura
L
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.
Gerstbrein
Beate
B
Frøkjaer-Jensen
Christian
C
Royal
Dewey C
DC
Mukherjee
Gargi
G
Royal
Mary Anne
MA
Xue
Jian
J
Schafer
William R
WR
Driscoll
Monica
M
D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D053503:Epithelial Sodium Channels; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009336:Necrosis; D009474:Neurons / Q000378:metabolism* / Q000502:physiology*; D015222:Sodium Channels / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014982:Xenopus laevis
D029742:Caenorhabditis elegans Proteins; D015220:Calcium Channels; C094927:Deg-1 protein, C elegans; D053503:Epithelial Sodium Channels; C115871:Mec-4 protein, C elegans; D008565:Membrane Proteins; D015222:Sodium Channels; D000584:Amiloride; D002118:Calcium