Members of the epithelial Na+ channel/degenerin (ENaC/DEG) family of ion channels have large extracellular domains with common structural features, including a β‐strand central core embraced by helical peripheral domains (referred to as finger, thumb and knuckle). We hypothesized that the peripheral helical domains serve as functional modules that facilitate interactions between ENaC and extracellular regulatory factors. In this study, we examined the properties of channels where the thumb domain was deleted from a specific subunit. We found that channels lacking the γ subunit thumb domain retained activity when expressed in Xenopus oocytes, but channels lacking the α or β subunit thumb domain had greatly reduced activity. Surface expression of channels lacking the thumb domain of any subunit was significantly lower than wild‐type. Channels with a γ subunit thumb domain deletion exhibited a loss of the Na+ self‐inhibition response, suggesting a high channel open probability in the presence of a high extracellular Na+ concentration. We conclude that the presence of the thumb domain in each ENaC subunit is required for optimal surface ENaC expression in oocytes. Furthermore, the presence of the γ thumb domain is required for the inhibitory response to extracellular Na+ (Na+ self‐inhibition).Support or Funding InformationSupported by NIH ES014701, DK051391 and P30 DK079307