Neurotoxic unc-8 mutants encode constitutively active DEG/ENaC channels that are blocked by divalent cations

Ying Wang, Cristina Matthewman, Lu Han, David M. Miller, Laura Bianchi

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Ion channels of the DEG/ENaC family can induce neurodegeneration under conditions in which they become hyperactivated. The Caenorhabditis elegans DEG/ENaC channel MEC-4(d) encodes a mutant channel with a substitution in the pore domain that causes swelling and death of the six touch neurons in which it is expressed. Dominant mutations in the C. elegans DEG/ENaC channel subunit UNC-8 result in uncoordinated movement. Here we show that this unc-8 movement defect is correlated with the selective death of cholinergic motor neurons in the ventral nerve cord. Experiments in Xenopus laevis ooctyes confirm that these mutant proteins, UNC-8(G387E) and UNC-8(A586T), encode hyperactivated channels that are strongly inhibited by extracellular calcium and magnesium. Reduction of extracellular divalent cations exacerbates UNC-8(G387E) toxicity in oocytes. We suggest that inhibition by extracellular divalent cations limits UNC-8 toxicity and may contribute to the selective death of neurons that express UNC-8 in vivo.

Original languageEnglish (US)
Pages (from-to)157-169
Number of pages13
JournalJournal of General Physiology
Volume142
Issue number2
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Physiology

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