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1Departments of Medicine and 3Cell Biology and Physiology, University of Pittsburgh, Pittsburgh 15261; and 2Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Submitted 5 March 2003 ; accepted in final form 21 May 2003
Epithelial sodium channels (ENaCs) are composed of three structurally
related subunits that form a tetrameric channel. The Xenopus laevis
oocyte expression system was used to identify regions within the ENaC
-subunit that confer a dominant negative phenotype on functional
expression of 
-ENaC to define domains that have a role in
subunit-subunit interactions. Coexpression of full-length mouse
-ENaC with either 1) the -subunit first
membrane-spanning domain and short downstream hydrophobic domain
(-M1H1); 2) -M1H1 and its downstream hydrophilic
extracellular loop (-M1H1-ECL); 3) the membrane-spanning
domain of a control type 2 transmembrane protein (glutamyl transpeptidase;
-GT) fused to the -ECL (-GT--ECL); 4) the
extracellular domain of a control type 1 transmembrane protein (Tac) fused to
the -subunit second membrane-spanning domain and short upstream
hydrophobic domain (Tac--H2M2); or 5) the -subunit
cytoplasmic COOH terminus (-Ct) significantly reduced
amiloride-sensitive Na+ currents in X. laevis oocytes.
Functional expression of Na+ channels was not inhibited when
full-length -ENaC was coexpressed with either 1)
the -ECL lacking a signal-anchor sequence, 2) -M1H1 and
-Ct expressed as a fusion protein, 3) full-length -GT,
or 4) full-length Tac. Furthermore, the expression of ROMK channels
was not inhibited when full-length ROMK was coexpressed with either
-M1H1-ECL or -Ct. Full-length FLAG-tagged -, -, or
-ENaC coimmunoprecipitated with myc-tagged -M1H1-ECL, whereas
wild-type -GT did not. These data suggest that multiple sites within
the -subunit participate in subunit-subunit interactions that are
required for proper assembly of the heterooligomeric ENaC complex.
amiloride-sensitive sodium channel; dominant negative mutants
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