THE NEMATODE DEGENERIN UNC-105 FORMS ION CHANNELS THAT ARE ACTIVATED BY DEGENERATION-CAUSING OR HYPERCONTRACTION-CAUSING MUTATIONS

Nematode degenerins have been implicated in touch sensitivity and othe r forms of mechanosensation. Certain mutations in several degenerin ge nes cause the swelling, vacuolation, and death of neurons, and other m utations in the muscle degenerin gene unc-105 cause hypercontraction. Here, we confirm that unc-105 encodes an ion channel and show that it is constitutively active when mutated. These mutations disrupt differe nt regions of the channel and have different effects on its gating. Th e UNC-105 channels are permeable to small monovalent cations but show voltage-dependent block by Ca2+ and Mg2+. Amiloride also produces volt age-dependent block, consistent with a single binding site 65% into th e electric field. Mammalian cells expressing the mutant channels accum ulate membranous whorls and multicompartment vacuoles, hallmarks of de generin-induced cell death across species.