The finding that C. elegans unc-79, unc-80, and nca-1;nca-2 double mutants were hypersensitive to acute ethanol exposure suggests that this pathway is important for determining ethanol sensitivity. As in vertebrates, UNC-79 and UNC-80 proteins are thought to regulate the NALCN-related leak channel encoded by nca-1 and nca-2 [32]. It was possible however that the ethanol phenotypes of unc-79 and unc-80 were due to additional, as yet undiscovered, roles of these genes. The fact that the nca-1;nca-2 double mutant exhibits the same ethanol hypersensitivity suggests that the normal function of this leak channel is indeed required for ethanol responses. Ethanol may directly modulate the nca-encoded leak channel or perhaps indirectly modulate the channel through an effect on unc-79 and unc-80. The ethanol hypersensitivity of Lightweight mice may also reflect defective NALCN function.
