title: Neurotoxic unc-8 mutants encode constitutively active DEG/ENaC channels that are blocked by divalent cations.
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.
authors.affiliation: Department of Physiology and Biophysics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Cristina
authors.initials: C
authors.lastname: Matthewman
authors.forename: Lu
authors.initials: L
authors.lastname: Han
authors.forename: Tyne
authors.initials: T
authors.lastname: Miller
authors.forename: David M
authors.initials: DM
authors.lastname: Miller
authors.forename: Laura
authors.initials: L
authors.lastname: Bianchi
mesh_terms: D000200:Action Potentials; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000494:pharmacology*; D016923:Cell Death / Q000235:genetics; D059329:Cholinergic Neurons / Q000378:metabolism / Q000502:physiology; D005799:Genes, Dominant; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008274:Magnesium / Q000494:pharmacology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism / Q000502:physiology; D009154:Mutation; D014981:Xenopus
chemical_list: D029742:Caenorhabditis elegans Proteins; C094927:Deg-1 protein, C elegans; D007473:Ion Channels; D008565:Membrane Proteins; C104078:unc-8 protein, C elegans; D008274:Magnesium; D002118:Calcium
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