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J. Biol. Chem., Vol. 276, Issue 2, 1326-1334, January 12, 2001
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From the Departments of Medicine, Physiology and
§ Pathology, School of Medicine, University of Pennsylvania
and Veterans Affairs Medical Center,
Philadelphia, Pennsylvania 19104
Epithelial sodium channels (ENaC) have a
crucial role in the regulation of extracellular fluid volume and blood
pressure. To study the structure of the pore region of ENaC, the
susceptibility of introduced cysteine residues to sulfhydryl-reactive
methanethiosulfonate derivatives
((2-aminoethyl)methanethiosulfonate hydrobromide (MTSEA) and
[(2-(trimethylammonium)ethyl]methanethiosulfonate bromide (MTSET))
and to Cd2+ was determined. Selected mutants within
the amino-terminal portion (
Epithelial Sodium Channel Pore Region
STRUCTURE AND ROLE IN GATING*
,,
Val569-Trp582) of the pore region
responded to MTSEA, MTSET, or Cd2+ with stimulation or
inhibition of whole cell Na+ current. The reactive residues
were not contiguous but were separated by 2-3 residues where
substituted cysteine residues did not respond to the reagents and line
one face of an -helix. The activation of S580C
mENaC by
MTSET was associated with a large increase in channel open probability.
Within the carboxyl-terminal portion (Ser583-Ser592) of the pore region, only
one mutation (S583C) conferred a rapid, nearly complete block by
MTSEA, MTSET, and Cd2+, whereas several other mutant
channels were partially blocked by MTSEA or Cd2+ but not by
MTSET. Our data suggest that the outer pore of ENaC is formed by an
-helix, followed by an extended region that forms a selectivity
filter. Furthermore, our data suggest that the pore region participates
in ENaC gating.
*
This work was supported in part by National Institutes of
Health Grants DK54354 and DK50268 and by the Department of Veterans Affairs.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.
Recipients of postdoctoral fellowship awards from the Cystic
Fibrosis Foundation.
¶
Present address and to whom correspondence should be
addressed: Renal Division, A919 Scaife Hall, 3550 Terrace St.,
Pittsburgh, PA 15213. Tel.: 412-647-3121; Fax: 412-647-6222; E-mail:
kleyman@pitt.edu.
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