A new subunit of the epithelial Na+ channel identifies regions involved in Na+ self-inhibition

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Abstract

The epithelial Na+ channel (ENaC) is the apical entry pathway for Na+ in many Na+-reabsorbing epithelia. ENaC is a heterotetrameric protein composed of homologous α, β, and γ subunits. Mutations in ENaC cause severe hypertension or salt wasting in humans; and consequently, ENaC activity is tightly controlled. According to the concept of Na+ self-inhibition, the extracellular Na+ ion itself can reduce ENaC activity. The molecular basis for Na+ self-inhibition is unknown. Here, we describe cloning of a new ENaC subunit from Xenopus laevis (εxENaC). εxENaC can replace αxENaC and formed functional, highly selective, amiloride-sensitive Na+ channels when coexpressed with βxENaC and γxENaC. Channels containing εxENaC showed strong inhibition by extracellular Na+. This Na+ self-inhibition was significantly slower than for αxENaC-containing channels. Using site-directed mutagenesis, we show that the proximal part of the large extracellular domain controls the speed of self-inhibition. This suggests that this region is involved in conformational changes during Na+ self-inhibition.

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Babini, E., Geisler, H. S., Siba, M., & Gründer, S. (2003). A new subunit of the epithelial Na+ channel identifies regions involved in Na+ self-inhibition. Journal of Biological Chemistry, 278(31), 28418–28426. https://doi.org/10.1074/jbc.M301315200

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