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.
