Deletion of α-subunit exon 11 of the epithelial Na+ channel reveals a regulatory module.

Am J Physiol Renal Physiol

Renal-Electrolyte Div., Univ. of Pittsburgh, 3550 Terrace St., Pittsburgh, PA 15261.

Published: March 2014

AI Article Synopsis

  • Epithelial Na(+) channel (ENaC) subunits (α, β, γ) are formed from mRNAs processed with 13 exons, and individual exons 3-12 were tested for their role in channel function.
  • Deletion of most exons led to loss of channel activity, except exon 11 in the α-subunit, which created hyperactive channels with increased current and open probability.
  • Exon 11 is crucial for regulating channel gating in the α-subunit, while deletions in β- or γ-subunit exons significantly reduced channel activity and surface expression.

Article Abstract

Epithelial Na(+) channel (ENaC) subunits (α, β, and γ) found in functional complexes are translated from mature mRNAs that are similarly processed by the inclusion of 13 canonical exons. We examined whether individual exons 3-12, encoding the large extracellular domain, are required for functional channel expression. Human ENaCs with an in-frame deletion of a single α-subunit exon were expressed in Xenopus oocytes, and their functional properties were examined by two-electrode voltage clamp. With the exception of exon 11, deletion of an individual exon eliminated channel activity. Channels lacking α-subunit exon 11 were hyperactive. Oocytes expressing this mutant exhibited fourfold greater amiloride-sensitive whole cell currents than cells expressing wild-type channels. A parallel fivefold increase in channel open probability was observed with channels lacking α-subunit exon 11. These mutant channels also exhibited a lost of Na(+) self-inhibition, whereas we found similar levels of surface expression of mutant and wild-type channels. In contrast, in-frame deletions of exon 11 from either the β- or γ-subunit led to a significant loss of channel activity, in association with a marked decrease in surface expression. Our results suggest that exon 11 within the three human ENaC genes encodes structurally homologous yet functionally diverse domains and that exon 11 in the α-subunit encodes a module that regulates channel gating.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949035PMC
http://dx.doi.org/10.1152/ajprenal.00587.2013DOI Listing

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