Defining an inhibitory domain in the gamma subunit of the epithelial sodium channel.

American Journal of Physiology. Renal Physiology
Christopher J PasseroThomas R Kleyman

Abstract

Proteases activate the epithelial sodium channel (ENaC) by cleaving the large extracellular domains of the α- and γ-subunits and releasing peptides with inhibitory properties. Furin and prostasin activate mouse ENaC by cleaving the γ-subunit at sites flanking a 43 residue inhibitory tract (γE144-K186). To determine whether there is a minimal inhibitory region within this 43 residue tract, we generated serial deletions in the inhibitory tract of the γ-subunit in channels resistant to cleavage by furin and prostasin. We found that partial or complete deletion of a short segment in the γ-subunit, R158-N171, enhanced channel activity. Synthetic peptides overlapping this segment in the γ-subunit further identified a key 11-mer tract, R158-F168 (RFLNLIPLLVF), which inhibited wild-type ENaC expressed in Xenopus laevis oocytes, and endogenous channels in mpkCCD cells and human airway epithelia. Further studies with amino acid-substituted peptides defined residues that are required for inhibition in this key 11-mer tract. The presence of the native γ inhibitory tract in ENaC weakened the intrinsic binding constant of the 11-mer peptide inhibitor, suggesting that the γ inhibitory tract and the 11-mer peptide interact at overlapping sites...Continue Reading

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Citations

Sep 8, 2010·The Journal of Biological Chemistry·Ossama B KashlanThomas R Kleyman
Apr 19, 2012·The Journal of Biological Chemistry·Ossama B KashlanThomas R Kleyman
Aug 4, 2012·The Journal of Biological Chemistry·Michael B ButterworthPatrick H Thibodeau
Jan 27, 2012·American Journal of Physiology. Cell Physiology·Yawar J QadriCatherine M Fuller
May 11, 2012·American Journal of Physiology. Renal Physiology·Naomi NiisatoYoshinori Marunaka
Jul 15, 2011·American Journal of Physiology. Renal Physiology·Ossama B Kashlan, Thomas R Kleyman
Oct 14, 2011·American Journal of Physiology. Renal Physiology·Christopher J PasseroThomas R Kleyman
Sep 28, 2014·The Journal of Physiology·Chong Da TanRobert Tarran
Mar 13, 2012·Experimental Cell Research·Ossama B Kashlan, Thomas R Kleyman
Sep 24, 2015·Protein Expression and Purification·Bharat G ReddyLawrence J DeLucas
Apr 25, 2015·Advances in Chronic Kidney Disease·Evan C RayThomas R Kleyman
Sep 27, 2018·ELife·Sigrid NorengIsabelle Baconguis
Jul 26, 2014·Journal of the American Society of Nephrology : JASN·Rikke M ZacharPer Svenningsen
May 17, 2019·The Journal of Biological Chemistry·Xue-Ping WangOssama B Kashlan
Oct 11, 2013·American Journal of Physiology. Renal Physiology·Shujie Shi, Thomas R Kleyman
Nov 10, 2017·Annual Review of Physiology·Thomas R KleymanRebecca P Hughey
Mar 27, 2016·The Journal of Biological Chemistry·Aram J Krauson, Marcelo D Carattino
Nov 14, 2019·American Journal of Physiology. Cell Physiology·Thomas R Kleyman, Douglas C Eaton

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