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

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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.

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