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-subunit of ENaC is more important for channel surface
expression than the 
-subunit
1 University Laboratory of Physiology, University of Oxford, Oxford OX1 3PT, United Kingdom; and 2 Institut für Zelluläre und Molekulare Physiologie, Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany
The amiloride-sensitive
epithelial sodium channel (ENaC) plays a critical role in fluid and
electrolyte homeostasis and is composed of three homologous subunits:
, 
, and 
. Only heteromultimeric channels made of ENaC
are efficiently expressed at the cell surface, resulting in maximally
amiloride-sensitive currents. To study the relative importance of
various regions of the - and -subunits for the expression of
functional ENaC channels at the cell surface, we constructed
hemagglutinin (HA)-tagged --chimeric subunits composed of -
and -subunit regions and coexpressed them with HA-tagged - and
-subunits in Xenopus laevis oocytes. The whole cell
amiloride-sensitive sodium current (
Iami) and
surface expression of channels were assessed in parallel using the
two-electrode voltage-clamp technique and a chemiluminescence assay.
Because coexpression of ENaC resulted in larger
Iami and surface expression compared with
coexpression of ENaC, we hypothesized that the -subunit is
more important for ENaC trafficking than the -subunit. Using
chimeras, we demonstrated that channel activity is largely preserved
when the highly conserved second cysteine rich domains (CRD2) of the
- and -subunits are exchanged. In contrast, exchanging the whole
extracellular loops of the - and the -subunits largely reduced
ENaC currents and ENaC expression in the membrane. This indicates that
there is limited interchangeability between molecular regions of the
two subunits. Interestingly, our chimera studies demonstrated that the
intracellular termini and the two transmembrane domains of ENaC are
more important for the expression of functional channels at the cell
surface than the corresponding regions of ENaC.
epithelial sodium channel domains; chimeras; whole cell amiloride-sensitive current; surface expression
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