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J. Biol. Chem., Vol. 277, Issue 51, 50098-50111, December 20, 2002
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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
External Nickel Inhibits Epithelial Sodium Channel by Binding to
Histidine Residues within the Extracellular Domains of
and 
Subunits and Reducing Channel Open Probability*
,
-
-
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.
*
This work was supported by National Institutes of Health
Grants DK51391 and DK54354.The costs of publication of this
article were defrayed in part by the
payment of page charges. The 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: 929 Scaife Hall,
Renal-Electrolyte Division, University of Pittsburgh, 3550 Terrace St.,
Pittsburgh, PA 15261. Tel.: 412-648-9295; Fax: 412-648-9166; E-mail:
shaohu@pitt.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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