|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 282, Issue 9, 6153-6160, March 2, 2007
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Epithelial Na+ Channels Are Fully Activated by Furin- and Prostasin-dependent Release of an Inhibitory Peptide from the 
-Subunit*
11
¶2
From the
Renal-Electrolyte Division and ¶Division of Pulmonary and Critical Care Medicine, Department of Medicine, and Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261
Epithelial sodium channels (ENaC) are expressed in the apical membrane of high resistance Na+ transporting epithelia and have a key role in regulating extracellular fluid volume and the volume of airway surface liquids. Maturation and activation of ENaC subunits involves furin-dependent cleavage of the ectodomain at two sites in the 
subunit and at a single site within the 
subunit. We now report that the serine protease prostasin further activates ENaC by inducing cleavage of the subunit at a site distal to the furin cleavage site. Dual cleavage of the subunit is predicted to release a 43-amino acid peptide. Channels with a subunit lacking this 43-residue tract have increased activity due to a high open probability. A synthetic peptide corresponding to the fragment cleaved from the subunit is a reversible inhibitor of endogenous ENaCs in mouse cortical-collecting duct cells and in primary cultures of human airway epithelial cells. Our results suggest that multiple proteases cleave ENaC subunits to fully activate the channel.
Received for publication, November 16, 2006 , and in revised form, December 19, 2006.
* This work was supported by National Institutes of Health Grants DK065161, P30 DK072506, and P50 DK54690 and by Cystic Fibrosis Foundation Grant R883CR02. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 These authors contributed equally to this work.
2 To whom correspondence should be addressed: Renal-Electrolyte Division, University of Pittsburgh, S933 Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261. Tel.: 412-383-8949; Fax: 412-383-8956; E-mail: hughey{at}dom.pitt.edu.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  V. A. Swystun, B. Renaux, F. Moreau, S. Wen, M. A. Peplowski, M. D. Hollenberg, and W. K. MacNaughton Serine proteases decrease intestinal epithelial ion permeability by activation of protein kinase C{zeta} Am J Physiol Gastrointest Liver Physiol, July 1, 2009; 297(1): G60 - G70. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. B. Maarouf, N. Sheng, J. Chen, K. L. Winarski, S. Okumura, M. D. Carattino, C. R. Boyd, T. R. Kleyman, and S. Sheng Novel Determinants of Epithelial Sodium Channel Gating within Extracellular Thumb Domains J. Biol. Chem., March 20, 2009; 284(12): 7756 - 7765. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. P. Korovkina, S. J. Stamnes, A. M. Brainard, and S. K. England Nardilysin convertase regulates the function of the maxi-K channel isoform mK44 in human myometrium Am J Physiol Cell Physiol, March 1, 2009; 296(3): C433 - C440. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Svenningsen, C. Bistrup, U. G. Friis, M. Bertog, S. Haerteis, B. Krueger, J. Stubbe, O. N. Jensen, H. C. Thiesson, T. R. Uhrenholt, et al. Plasmin in Nephrotic Urine Activates the Epithelial Sodium Channel J. Am. Soc. Nephrol., February 1, 2009; 20(2): 299 - 310. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. R. Kleyman and R. P. Hughey Plasmin and Sodium Retention in Nephrotic Syndrome J. Am. Soc. Nephrol., February 1, 2009; 20(2): 233 - 234. [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. Butterworth, R. S. Edinger, R. A. Frizzell, and J. P. Johnson Regulation of the epithelial sodium channel by membrane trafficking Am J Physiol Renal Physiol, January 1, 2009; 296(1): F10 - F24. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Passero, G. M. Mueller, H. Rondon-Berrios, S. P. Tofovic, R. P. Hughey, and T. R. Kleyman Plasmin Activates Epithelial Na+ Channels by Cleaving the {gamma} Subunit J. Biol. Chem., December 26, 2008; 283(52): 36586 - 36591. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Butterworth, O. A. Weisz, and J. P. Johnson Some Assembly Required: Putting the Epithelial Sodium Channel Together J. Biol. Chem., December 19, 2008; 283(51): 35305 - 35309. [Full Text] [PDF]
|
|
|
|
|
|
K. W. Rickert, P. Kelley, N. J. Byrne, R. E. Diehl, D. L. Hall, A. M. Montalvo, J. C. Reid, J. M. Shipman, B. W. Thomas, S. K. Munshi, et al. Structure of Human Prostasin, a Target for the Regulation of Hypertension J. Biol. Chem., December 12, 2008; 283(50): 34864 - 34872. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Ruffieux-Daidie, O. Poirot, S. Boulkroun, F. Verrey, S. Kellenberger, and O. Staub Deubiquitylation Regulates Activation and Proteolytic Cleavage of ENaC J. Am. Soc. Nephrol., November 1, 2008; 19(11): 2170 - 2180. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Yu, M. N. Helms, Q. Yue, and D. C. Eaton Single-channel analysis of functional epithelial sodium channel (ENaC) stability at the apical membrane of A6 distal kidney cells Am J Physiol Renal Physiol, November 1, 2008; 295(5): F1519 - F1527. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Garcia-Caballero, Y. Dang, H. He, and M. J. Stutts ENaC Proteolytic Regulation by Channel-activating Protease 2 J. Gen. Physiol., October 27, 2008; 132(5): 521 - 535. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Knight, D. M. Wentzlaff, and P. M. Snyder Intracellular Sodium Regulates Proteolytic Activation of the Epithelial Sodium Channel J. Biol. Chem., October 10, 2008; 283(41): 27477 - 27482. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Bhalla and K. R. Hallows Mechanisms of ENaC Regulation and Clinical Implications J. Am. Soc. Nephrol., October 1, 2008; 19(10): 1845 - 1854. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Nesterov, A. Dahlmann, M. Bertog, and C. Korbmacher Trypsin can activate the epithelial sodium channel (ENaC) in microdissected mouse distal nephron Am J Physiol Renal Physiol, October 1, 2008; 295(4): F1052 - F1062. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Diakov, K. Bera, M. Mokrushina, B. Krueger, and C. Korbmacher Cleavage in the {gamma}-subunit of the epithelial sodium channel (ENaC) plays an important role in the proteolytic activation of near-silent channels J. Physiol., October 1, 2008; 586(19): 4587 - 4608. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Carattino, R. P. Hughey, and T. R. Kleyman Proteolytic Processing of the Epithelial Sodium Channel {gamma} Subunit Has a Dominant Role in Channel Activation J. Biol. Chem., September 12, 2008; 283(37): 25290 - 25295. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Kamenicky, S. Viengchareun, A. Blanchard, G. Meduri, P. Zizzari, M. Imbert-Teboul, A. Doucet, P. Chanson, and M. Lombes Epithelial Sodium Channel Is a Key Mediator of Growth Hormone-Induced Sodium Retention in Acromegaly Endocrinology, July 1, 2008; 149(7): 3294 - 3305. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Frindt, Z. Ergonul, and L. G. Palmer Surface Expression of Epithelial Na Channel Protein in Rat Kidney J. Gen. Physiol., June 1, 2008; 131(6): 617 - 627. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Fejes-Toth, G. Frindt, A. Naray-Fejes-Toth, and L. G. Palmer Epithelial Na+ channel activation and processing in mice lacking SGK1 Am J Physiol Renal Physiol, June 1, 2008; 294(6): F1298 - F1305. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. J. McDonald A new SGK1 knockout mouse Am J Physiol Renal Physiol, June 1, 2008; 294(6): F1296 - F1297. [Full Text] [PDF]
|
|
|
|
|
|
M. Lu, F. Echeverri, D. Kalabat, B. Laita, D. S. Dahan, R. D. Smith, H. Xu, L. Staszewski, J. Yamamoto, J. Ling, et al. Small Molecule Activator of the Human Epithelial Sodium Channel J. Biol. Chem., May 2, 2008; 283(18): 11981 - 11994. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Myerburg, E. E. McKenna, C. J. Luke, R. A. Frizzell, T. R. Kleyman, and J. M. Pilewski Prostasin expression is regulated by airway surface liquid volume and is increased in cystic fibrosis Am J Physiol Lung Cell Mol Physiol, May 1, 2008; 294(5): L932 - L941. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Harris, A. Garcia-Caballero, M. J. Stutts, D. Firsov, and B. C. Rossier Preferential Assembly of Epithelial Sodium Channel (ENaC) Subunits in Xenopus Oocytes: ROLE OF FURIN-MEDIATED ENDOGENOUS PROTEOLYSIS J. Biol. Chem., March 21, 2008; 283(12): 7455 - 7463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Kabra, K. K. Knight, R. Zhou, and P. M. Snyder Nedd4-2 Induces Endocytosis and Degradation of Proteolytically Cleaved Epithelial Na+ Channels J. Biol. Chem., March 7, 2008; 283(10): 6033 - 6039. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Picard, D. Eladari, S. El Moghrabi, C. Planes, S. Bourgeois, P. Houillier, Q. Wang, M. Burnier, G. Deschenes, M. A. Knepper, et al. Defective ENaC Processing and Function in Tissue Kallikrein-deficient Mice J. Biol. Chem., February 22, 2008; 283(8): 4602 - 4611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Adebamiro, Y. Cheng, U. S. Rao, H. Danahay, and R. J. Bridges A Segment of {gamma} ENaC Mediates Elastase Activation of Na+ Transport J. Gen. Physiol., November 26, 2007; 130(6): 611 - 629. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. M. Mueller, O. B. Kashlan, J. B. Bruns, A. B. Maarouf, M. Aridor, T. R. Kleyman, and R. P. Hughey Epithelial Sodium Channel Exit from the Endoplasmic Reticulum Is Regulated by a Signal within the Carboxyl Cytoplasmic Domain of the {alpha} Subunit J. Biol. Chem., November 16, 2007; 282(46): 33475 - 33483. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. P. Hughey and T. R. Kleyman Functional cross talk between ENaC and pendrin Am J Physiol Renal Physiol, November 1, 2007; 293(5): F1439 - F1440. [Full Text] [PDF]
|
|
|
|
|
|
X. Chen, G. Polleichtner, I. Kadurin, and S. Grunder Zebrafish Acid-sensing Ion Channel (ASIC) 4, Characterization of Homo- and Heteromeric Channels, and Identification of Regions Important for Activation by H+ J. Biol. Chem., October 19, 2007; 282(42): 30406 - 30413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. H. Kim, V. Pech, K. B. Spencer, W. H. Beierwaltes, L. A. Everett, E. D. Green, W. Shin, J. W. Verlander, R. L. Sutliff, and S. M. Wall Reduced ENaC protein abundance contributes to the lower blood pressure observed in pendrin-null mice Am J Physiol Renal Physiol, October 1, 2007; 293(4): F1314 - F1324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Falin and C. U. Cotton Acute Downregulation of ENaC by EGF Involves the PY Motif and Putative ERK Phosphorylation Site J. Gen. Physiol., August 27, 2007; 130(3): 313 - 328. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |