Gain-of-function variant of the human epithelial sodium channel

Chen J, Kleyman TR, Sheng S. Gain-of-function variant of the human epithelial sodium channel. Am J Physiol Renal Physiol 304: F207-F213, 2013. First published November 7, 2012; doi:10.1152/ajprenal.00563.2012.-Epithelial Na+ channel (ENaC) mutations are associated with several human disorders, underscoring the importance of these channels in human health. Recent human genome sequencing projects have revealed a large number of ENaC gene variations, several of which have been found in individuals with salt-sensitive hypertension, cystic fibrosis, and other disorders. However, the functional consequences of most variants are unknown. In this study, we used the Xenopus oocyte expression system to examine the functional properties of a human ENaC variant. Oocytes expressing alpha beta gamma L511Q human ENaCs showed 4.6-fold greater amiloride-sensitive currents than cells expressing wild-type channels. The gamma L511Q variant did not significantly alter channel surface expression. Single channel recordings revealed that the variant had fourfold higher open probability than wild type. In addition, gamma L511Q largely eliminated the Na+ self-inhibition response, which reflects a down-regulation of ENaC open probability by extracellular Na+. Moreover, gamma L511Q diminished chymotrypsin-induced activation of the mutant channel. We conclude that gamma L511Q is a gain-of-function human ENaC variant. Our results suggest that gamma L511Q enhances ENaC activity by increasing channel open probability and dampens channel regulation by extracellular Na+ and proteases.