Intersubunit interactions between mutant DEG/ENaCs induce synthetic neurotoxicity

W. Zhang, Laura Bianchi, W. H. Lee, Y. Wang, S. Israel, M. Driscoll

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 Ca2+ currents (with a disproportionate increase in Ca2+ 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 Ca2+ current levels may be decisive factors in tipping the balance between neuronal survival and necrosis.

Original languageEnglish
Pages (from-to)1794-1803
Number of pages10
JournalCell Death and Differentiation
Volume15
Issue number11
DOIs
StatePublished - Aug 4 2008

Fingerprint

Degenerin Sodium Channels
Amiloride
Necrosis
Ion Channels
Acid Sensing Ion Channels
Poisons
Caenorhabditis elegans
Touch
Invertebrates
Xenopus
Acidosis
Neurodegenerative Diseases
Oocytes
Protons
Ischemia
Stroke
Phenotype
Mutation
Wounds and Injuries
Brain

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Intersubunit interactions between mutant DEG/ENaCs induce synthetic neurotoxicity. / Zhang, W.; Bianchi, Laura; Lee, W. H.; Wang, Y.; Israel, S.; Driscoll, M.

In: Cell Death and Differentiation, Vol. 15, No. 11, 04.08.2008, p. 1794-1803.

Research output: Contribution to journalArticle

Zhang, W. ; Bianchi, Laura ; Lee, W. H. ; Wang, Y. ; Israel, S. ; Driscoll, M. / Intersubunit interactions between mutant DEG/ENaCs induce synthetic neurotoxicity. In: Cell Death and Differentiation. 2008 ; Vol. 15, No. 11. pp. 1794-1803.
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