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

J. Biol. Chem., Vol. 279, Issue 11, 9743-9749, March 12, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/11/9743    most recent M311952200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sheng, S. Articles by Kleyman, T. R. Search for Related Content PubMed PubMed Citation Articles by Sheng, S. Articles by Kleyman, T. R. Social Bookmarking                      What's this?

Extracellular Histidine Residues Crucial for Na⁺ Self-inhibition of Epithelial Na⁺ Channels^*

Shaohu Sheng, James B. Bruns, and Thomas R. Kleyman

From the Renal-Electrolyte Division, Department of Medicine and the Department of Cell Biology and Physiology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

Epithelial Na⁺ channels (ENaC) participate in the regulation of extracellular fluid volume homeostasis and blood pressure. Channel activity is regulated by both extracellular and intracellular Na⁺. The down-regulation of ENaC activity by external Na⁺ is referred to as Na⁺ self-inhibition. We investigated the structural determinants of Na⁺ self-inhibition by expressing wild-type or mutant ENaCs in Xenopus oocytes and analyzing changes in whole-cell Na⁺ currents following a rapid increase of bath Na⁺ concentration. Our results indicated that wild-type mouse ENaC has intrinsic Na⁺ self-inhibition similar to that reported for human, rat, and Xenopus ENaCs. Mutations at His²³⁹ (H239R, H239D, and H239C) in the extracellular loop of the ENaC subunit prevented Na⁺ self-inhibition whereas mutations of the corresponding His²⁸² in ENaC (H282D, H282R, H282W, and H282C) significantly enhanced Na⁺ self-inhibition. These results suggest that these two histidine residues within the extracellular loops are crucial structural determinants for Na⁺ self-inhibition.

Received for publication, October 31, 2003 , and in revised form, December 15, 2003.

^* This work was supported by grants from the National Institutes of Health (DK54354) and the Cystic Fibrosis Foundation (Kleyma03PO). 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.

To whom correspondence should be addressed: Renal-Electrolyte Division, University of Pittsburgh, 3550 Terrace St., Pittsburgh, PA 15261. Tel.: 412-648-9295; Fax: 412-648-9166; E-mail: shaohu{at}pitt.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				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]

				D. M. Collier and P. M. Snyder Extracellular Protons Regulate Human ENaC by Modulating Na+ Self-inhibition J. Biol. Chem., January 9, 2009; 284(2): 792 - 798. [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. Bize and J.-D. Horisberger Sodium self-inhibition of human epithelial sodium channel: selectivity and affinity of the extracellular sodium sensing site Am J Physiol Renal Physiol, October 1, 2007; 293(4): F1137 - F1146. [Abstract] [Full Text] [PDF]

				S. Sheng, A. B. Maarouf, J. B. Bruns, R. P. Hughey, and T. R. Kleyman Functional Role of Extracellular Loop Cysteine Residues of the Epithelial Na+ Channel in Na+ Self-inhibition J. Biol. Chem., July 13, 2007; 282(28): 20180 - 20190. [Abstract] [Full Text] [PDF]

				L. Yu, D. C. Eaton, and M. N. Helms Effect of divalent heavy metals on epithelial Na+ channels in A6 cells Am J Physiol Renal Physiol, July 1, 2007; 293(1): F236 - F244. [Abstract] [Full Text] [PDF]

				M. D. Carattino, W. Liu, W. G. Hill, L. M. Satlin, and T. R. Kleyman Lack of a role of membrane-protein interactions in flow-dependent activation of ENaC Am J Physiol Renal Physiol, July 1, 2007; 293(1): F316 - F324. [Abstract] [Full Text] [PDF]

				S. Sheng, M. D. Carattino, J. B. Bruns, R. P. Hughey, and T. R. Kleyman Furin cleavage activates the epithelial Na+ channel by relieving Na+ self-inhibition Am J Physiol Renal Physiol, June 1, 2006; 290(6): F1488 - F1496. [Abstract] [Full Text] [PDF]

				H.-L. Ji, X.-F. Su, S. Kedar, J. Li, P. Barbry, P. R. Smith, S. Matalon, and D. J. Benos {delta}-Subunit Confers Novel Biophysical Features to {alpha}beta{gamma}-Human Epithelial Sodium Channel (ENaC) via a Physical Interaction J. Biol. Chem., March 24, 2006; 281(12): 8233 - 8241. [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]

				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]

				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]

				L. Chen, C. M. Fuller, T. R. Kleyman, and S. Matalon Mutations in the extracellular loop of {alpha}-rENaC alter sensitivity to amiloride and reactive species Am J Physiol Renal Physiol, June 1, 2004; 286(6): F1202 - F1208. [Abstract] [Full Text] [PDF]

				R. P. Hughey, J. B. Bruns, C. L. Kinlough, K. L. Harkleroad, Q. Tong, M. D. Carattino, J. P. Johnson, J. D. Stockand, and T. R. Kleyman Epithelial Sodium Channels Are Activated by Furin-dependent Proteolysis J. Biol. Chem., April 30, 2004; 279(18): 18111 - 18114. [Abstract] [Full Text] [PDF]