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J. Biol. Chem., Vol. 279, Issue 30, 31687-31696, July 23, 2004

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Extracellular Zn²⁺ Activates Epithelial Na⁺ Channels by Eliminating Na⁺ Self-inhibition^*

Shaohu Sheng, Clint J. Perry, and Thomas R. Kleyman¶

From the Renal-Electrolyte Division, Department of Medicine, and ^¶Department of Cell Biology and Physiology, School of Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, Pennsylvania 15261

Inhibition of epithelial Na⁺ channel (ENaC) activity by high concentrations of extracellular Na⁺ is referred to as Na⁺ self-inhibition. We investigated the effects of external Zn²⁺ on whole cell Na⁺ currents and on the Na⁺ self-inhibition response in Xenopus oocytes expressing mouse ENaC. Na⁺ self-inhibition was examined by analyzing inward current decay from a peak current to a steady-state current following a fast switching of a low Na⁺ (1 mM) bath solution to a high Na⁺ (110 mM) solution. Our results indicate that external Zn²⁺ rapidly and reversibly activates ENaC in a dose-dependent manner with an estimated EC₅₀ of 2 µM. External Zn²⁺ in the high Na⁺ bath also prevents or reverses Na⁺ self-inhibition with similar affinity. Zn²⁺ activation is dependent on extracellular Na⁺ concentration and is absent in ENaCs containing H239 mutations that eliminate Na⁺ self-inhibition and in S580C following covalent modification by a sulfhydryl-reactive reagent that locks the channels in a fully open state. In contrast, external Ni²⁺ inhibition of ENaC currents appears to be additive to Na⁺ self-inhibition when Ni²⁺ is present in the high Na⁺ bath. Pretreatment of oocytes with Ni²⁺ in a low Na⁺ bath also prevents the current decay following a switch to a high Na⁺ bath but rendered the currents below the control steady-state level measured in the absence of Ni²⁺ pretreatment. Our results suggest that external Zn²⁺ activates ENaC by relieving the channel from Na⁺ self-inhibition, and that external Ni²⁺ mimics or masks Na⁺ self-inhibition.

Received for publication, May 11, 2004

^* This work was supported by National Institutes of Health Grant DK54354 and by Cystic Fibrosis Foundation Grant 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: 412-383-8956; E-mail: shaohu{at}pitt.edu.

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