The epithelial amiloride-sensitive sodium channel constitutes the rate limiting step for sodium reabsorbtion by the epithelial lining the distal part of the kidney tubule, the urinary bladder and the distal colon. Reabsorbtion of sodium through this channel, which is regulated by hormones such as aldosterone and vasopressin, is one of the essential mechanisms involved in the regulation of sodium balance, blood volume and blood pressure. Here we isolate a DNA from epithelial cells of rat distal colon and identify it by functional expression of an amiloride-sensitive sodium current in Xenopus oocyte. The deduced polypeptide (698 amino acids) has at least two putative transmembrane segments. Expression of this protein in Xenopus oocytes reconstitutes the functional properties of the highly selective amiloride-sensitive, epithelial sodium channel. The gene encoding this rat sodium channel subunit shares significant sequence similarity with mec-4 and deg-1, members of a family of Caenorhabditis elegans genes involved in sensory touch transduction and, when mutated, neuronal degeneration. We propose that the gene products of these three genes are members of a gene family coding for cation channels.