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Am J Physiol Renal Physiol (November 21, 2007). doi:10.1152/ajprenal.00399.2007
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Submitted on August 29, 2007
Accepted on November 19, 2007

Defining an inhibitory domain in the alpha subunit of the epithelial sodium channel

Marcelo D. Carattino1*, Christopher J. Passero1, Carlos A Steren2, Ahmad B Maarouf1, Joseph M Pilewski3, Mike M Myerburg1, Rebecca P. Hughey4, and Thomas R Kleyman5

1 Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
2 Chemistry, University of Tennessee, Knoxville, Tennessee, United States
3 Division Pulm Allergy Crit Care Medicine, University Pittsburgh Sch Med, Pittsburgh, Pennsylvania, United States
4 Renal-Electrolyte Div/ Dept of Med, Univ of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
5 Renal-Electrolyte Division, Univ Pittsburgh, Pittsburgh, Pennsylvania, United States; , United States

* To whom correspondence should be addressed. E-mail: carattinom{at}dom.pitt.edu.

Epithelial sodium channels (ENaC) are processed by proteases as they transit the biosynthetic pathway. We recently observed that furin-dependent processing of the {alpha} subunit of ENaC at two sites within its extracellular domain is required for channel activation due to release of a 26-residue inhibitory domain. While channels with {alpha} subunits lacking the furin sites are not cleaved and have very low activity, channels lacking the furin sites as well as the tract between these sites ({alpha}D206-R231) are active. We analyzed channels with a series of deletions in the tract {alpha}D206-R231 and lacking the {alpha} subunit furin consensus sites in Xenopus laevis oocytes. We found an eight-residue tract that, when deleted, restored channel activity to the level found in oocytes expressing wild type ENaC. A synthetic peptide, LPHPLQRL, representing the tract {alpha}L211-L218 inhibited wild type ENaC expressed in oocytes with an IC50 of 0.9 µM, and inhibited channels expressed in collecting duct cells and human primary airway epithelial cells with IC50s of between ~50 to 100 µM. Analyses of peptides with deletions within this inhibitory tract indicate that eight residues is the minimal backbone length that is required for ENaC inhibition. Analyses of 8-mer peptides with conserved and non-conserved substitutions suggest that L1, P2, H3, P4, and L8 are required for inhibitory activity. Our findings suggest that this eight-residue tract is a key conserved inhibitory domain that provides epithelial cells with a reserve of channels that can be activated as required by proteases.




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