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J. Biol. Chem., Vol. 277, Issue 51, 50098-50111, December 20, 2002

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External Nickel Inhibits Epithelial Sodium Channel by Binding to Histidine Residues within the Extracellular Domains of  and  Subunits and Reducing Channel Open Probability^*

Shaohu Sheng, Clint J. Perry, and Thomas R. Kleyman^§

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

Epithelial sodium channels (ENaC) are regulated by various intracellular and extracellular factors including divalent cations. We studied the inhibitory effect and mechanism of external Ni²⁺ on cloned mouse -- ENaC expressed in Xenopus oocytes. Ni²⁺ reduced amiloride-sensitive Na⁺ currents of the wild type mouse ENaC in a dose-dependent manner. The Ni²⁺ block was fast and partially reversible at low concentrations and irreversible at high concentrations. ENaC inhibition by Ni²⁺ was accompanied by moderate inward rectification at concentrations higher than 0.1 mM. ENaC currents were also blocked by the histidine-reactive reagent diethyl pyrocarbonate. Pretreatment of the oocytes with the reagent reduced Ni²⁺ inhibition of the remaining current. Mutations at His²⁸² and His²³⁹ located within the extracellular loops significantly decreased Ni²⁺ inhibition of ENaC currents. The mutation H282D or double mutations H282R/H239R eliminated Ni²⁺ block. All mutations at His²³⁹ eliminated Ni²⁺-induced inward current rectification. Ni²⁺ block was significantly enhanced by introduction of a histidine at Arg²⁸⁰. Lowering extracellular pH to 5.5 and 4.4 decreased or eliminated Ni²⁺ block. Although H282C-- channels were partially inhibited by the sulfhydryl-reactive reagent [2-(trimethylammonium)ethyl] methanethiosulfonate bromide (MTSET), -- H239C channels were insensitive to MTSET. From patch clamp studies, Ni²⁺ did not affect unitary current but decreased open probability when perfused into the recording pipette. Our results suggest that external Ni²⁺ reduces ENaC open probability by binding to a site consisting of His²⁸² and His²³⁹ and that these histidine residues may participate in ENaC gating.

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