ABERRANT ion channel activity plays a causative role in several human disorders1-3. Inappropriately regulated channel activity also appears to be the basis for neurodegeneration induced by dominant mutations of Caenorhabditis elegans mec-4 (mec-4(d)), a member of the degenerin gene family postulated to encode a subunit of a mechanosensory channel4. The degenerin gene family has been defined by two C. elegans genes, mec-4 and deg-1 (ref. 5), which can mutate to gain-of-function alleles that induce degeneration of specific groups of neurons. A related mammalian gene, rat alpha-rENaC, induces an amiloride-sensitive Na+ current when introduced to Xenopus oocytes6, strongly suggesting that degenerin genes encode ion channel proteins. Deduced amino-acid sequences of the degenerins include two predicted membrane-spanning domains6,7. Here we show that conserved amino acids within the second membrane-spanning domain (MSDII) are critical for MEC-4 activity and that specific substitutions within MSDII, whether encoded in cis or in trans to a mec-4(d) mutation, block or delay the onset of degeneration. Remarkably, MSDII from two other family members, C. elegans deg-1 (ref. 5) and rat alpha-rENaC (ref. 6), can functionally substitute for MEC-4 MSDII in chimaeric proteins. Our results support a structural model for a mechanosensory channel in which multiple MEC-4 subunits are oriented such that MSDII lines the channel pore, and a neurodegeneration model in which aberrant ion flow through this channel is a key event.