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

Wang Y, Matthewman C, Han L, Miller T, Miller DM, Bianchi L
J Gen Physiol. 2013 142 (2): 157-69

PMID: 23898007 · PMCID: PMC3727304 · DOI:10.1085/jgp.201310974

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.

MeSH Terms (14)

Action Potentials Animals Caenorhabditis elegans Caenorhabditis elegans Proteins Calcium Cell Death Cholinergic Neurons Genes, Dominant Ion Channels Magnesium Membrane Proteins Motor Neurons Mutation Xenopus

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