HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 543/2/413    most recent 2002.022020v2 2002.022020v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kellenberger, S. Articles by Schild, L. Search for Related Content PubMed PubMed Citation Articles by Kellenberger, S. Articles by Schild, L.

An external site controls closing of the epithelial Na⁺ channel ENaC

Stephan Kellenberger, Ivan Gautschi and Laurent Schild

Members of the ENaC/degenerin family of ion channels include the epithelial sodium channel (ENaC), acid-sensing ion channels (ASICs) and the nematode Caenorhabditis elegans degenerins. These channels are activated by a variety of stimuli such as ligands (ASICs) and mechanical forces (degenerins), or otherwise are constitutively active (ENaC). Despite their functional heterogeneity, these channels might share common basic mechanisms for gating. Mutations of a conserved residue in the extracellular loop, namely the 'degenerin site' activate all members of the ENaC/degenerin family. Chemical modification of a cysteine introduced in the degenerin site of rat ENaC (S518C) by the sulfhydryl reagents MTSET or MTSEA, results in a ~3-fold increase in the open probability. This effect is due to an 8-fold shortening of channel closed times and an increase in the number of long openings. In contrast to the intracellular gating domain in the N-terminus which is critical for channel opening, the intact extracellular degenerin site is necessary for normal channel closing, as illustrated by our observation that modification of S518C destabilises the channel closed state. The modification by the sulfhydryl reagents is state- and size-dependent consistent with a conformational change of the degenerin site during channel opening and closing. We propose that the intracellular and extracellular modulatory sites act on a common channel gate and control the activity of ENaC at the cell surface.

This article has been cited by other articles:

				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. Althaus, R. Bogdan, W. G. Clauss, and M. Fronius Mechano-sensitivity of epithelial sodium channels (ENaCs): laminar shear stress increases ion channel open probability FASEB J, August 1, 2007; 21(10): 2389 - 2399. [Abstract] [Full Text] [PDF]

				A. L. Brown, S. M. Fernandez-Illescas, Z. Liao, and M. B. Goodman Gain-of-Function Mutations in the MEC-4 DEG/ENaC Sensory Mechanotransduction Channel Alter Gating and Drug Blockade J. Gen. Physiol., January 29, 2007; 129(2): 161 - 173. [Abstract] [Full Text] [PDF]

				Y. Pfister, I. Gautschi, A.-N. Takeda, M. van Bemmelen, S. Kellenberger, and L. Schild A Gating Mutation in the Internal Pore of ASIC1a J. Biol. Chem., April 28, 2006; 281(17): 11787 - 11791. [Abstract] [Full Text] [PDF]

				L.-M. Yang, R. Rinke, and C. Korbmacher Stimulation of the Epithelial Sodium Channel (ENaC) by cAMP Involves Putative ERK Phosphorylation Sites in the C Termini of the Channel's beta- and {gamma}-Subunit J. Biol. Chem., April 14, 2006; 281(15): 9859 - 9868. [Abstract] [Full Text] [PDF]

				M. Vukicevic, G. Weder, A. Boillat, A. Boesch, and S. Kellenberger Trypsin Cleaves Acid-sensing Ion Channel 1a in a Domain That Is Critical for Channel Gating J. Biol. Chem., January 13, 2006; 281(2): 714 - 722. [Abstract] [Full Text] [PDF]

				J. Loffing and L. Schild Functional Domains of the Epithelial Sodium Channel J. Am. Soc. Nephrol., November 1, 2005; 16(11): 3175 - 3181. [Full Text] [PDF]

				D. Cucu, J. Simaels, J. Eggermont, W. Van Driessche, and W. Zeiske Opposite effects of Ni2+ on Xenopus and rat ENaCs expressed in Xenopus oocytes Am J Physiol Cell Physiol, October 1, 2005; 289(4): C946 - C958. [Abstract] [Full Text] [PDF]

				S. Kellenberger, I. Gautschi, Y. Pfister, and L. Schild Intracellular Thiol-mediated Modulation of Epithelial Sodium Channel Activity J. Biol. Chem., March 4, 2005; 280(9): 7739 - 7747. [Abstract] [Full Text] [PDF]

				M. D. Carattino, S. Sheng, and T. R. Kleyman Mutations in the Pore Region Modify Epithelial Sodium Channel Gating by Shear Stress J. Biol. Chem., February 11, 2005; 280(6): 4393 - 4401. [Abstract] [Full Text] [PDF]

				A. Diakov and C. Korbmacher A Novel Pathway of Epithelial Sodium Channel Activation Involves a Serum- and Glucocorticoid-inducible Kinase Consensus Motif in the C Terminus of the Channel's {alpha}-Subunit J. Biol. Chem., September 10, 2004; 279(37): 38134 - 38142. [Abstract] [Full Text] [PDF]

				S. Sheng, C. J. Perry, and T. R. Kleyman Extracellular Zn2+ Activates Epithelial Na+ Channels by Eliminating Na+ Self-inhibition J. Biol. Chem., July 23, 2004; 279(30): 31687 - 31696. [Abstract] [Full Text] [PDF]

				H.-L. Ji and D. J. Benos Degenerin Sites Mediate Proton Activation of {delta}{beta}{gamma}-Epithelial Sodium Channel J. Biol. Chem., June 25, 2004; 279(26): 26939 - 26947. [Abstract] [Full Text] [PDF]

				S. Kellenberger, I. Gautschi, and L. Schild Mutations in the Epithelial Na+ Channel ENaC Outer Pore Disrupt Amiloride Block by Increasing Its Dissociation Rate Mol. Pharmacol., October 1, 2003; 64(4): 848 - 856. [Abstract] [Full Text] [PDF]