RRC ID 4323
Author Zhang W, Bianchi L, Lee WH, Wang Y, Israel S, Driscoll M.
Title Intersubunit interactions between mutant DEG/ENaCs induce synthetic neurotoxicity.
Journal Cell Death Differ.
Abstract Ion channel hyperactivation can result in neuronal loss in injury, stroke and neurodegenerative disease. Acidosis-associated hyperactivation of the Degenerin/epithelial amiloride-sensitive Na(+) channel (DEG/ENaC) acid-sensing ion channel 1a (ASIC1a), a proton-gated channel expressed in the mammalian brain, contributes significantly to neuronal loss in ischemia. Analogously, in invertebrates, genetic hyperactivation of the Caenorhabditis elegans mechanosensory (MEC) channel (MEC-4(d)) of the DEG/ENaC ion channel superfamily induces neuronal necrosis. Similarly substituted MEC-10(d) mutant subunits of the same MEC channel are only marginally neurotoxic, and we therefore exploited the weak necrosis phenotype of mec-10(d) lines to screen for novel extragenic mutations that enhance neuronal death. Here, we report on one mec-10(d) necrosis enhancer, which we show is MEC-4 variant MEC-4(A149V). MEC-4(A149V) executes normal MEC-4 function in touch sensation and does not induce necrosis on its own, but rather combines with MEC-10(d) to create a strongly neurotoxic channel. The MEC-4(A149V)+MEC-10(d) channel conducts elevated Na(+) and Ca(2+) currents (with a disproportionate increase in Ca(2+) current) in the Xenopus oocyte expression system, and exhibits altered binding of the channel inhibitor amiloride. Our data document the first example of synergistically toxic intersubunit interactions in the DEG/ENaC channel class and provide evidence that Ca(2+) current levels may be decisive factors in tipping the balance between neuronal survival and necrosis.
Volume 15(11)
Pages 1794-803
Published 2008-11
DOI 10.1038/cdd.2008.114
PII cdd2008114
PMID 18670436
MeSH Amino Acid Sequence Animals Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / chemistry Caenorhabditis elegans Proteins / metabolism* Calcium / metabolism Calreticulin / metabolism Conserved Sequence Epithelial Sodium Channels / chemistry Epithelial Sodium Channels / metabolism* Genes, Dominant Genes, Helminth Ion Channel Gating Membrane Proteins / chemistry Membrane Proteins / metabolism Molecular Sequence Data Mutant Proteins / chemistry Mutant Proteins / metabolism* Necrosis Nerve Degeneration / metabolism* Protein Binding Protein Structure, Tertiary Protein Subunits / chemistry Protein Subunits / metabolism* Sensation Sodium / metabolism Sodium Channels / chemistry Sodium Channels / metabolism* Touch
IF 8.0
Times Cited 11
WOS Category BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY
Resource
C.elegans tm1552