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J. Biol. Chem., Vol. 276, Issue 42, 38755-38761, October 19, 2001
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From the Departments of Members of the degenerin/epithelial
Na+ channel superfamily of ion channels subserve many
functions, ranging from whole body sodium handling to mechanoelectrical
transduction. We studied brain Na+ channel 2 (BNaC-2) in
planar lipid bilayers to examine its single channel properties and
regulation by Ca2+. Upon incorporation of vesicles made
from membranes of oocytes expressing either wild-type (WT) BNaC-2 or
BNaC-2 with a gain-of-function (GF) point mutation (G433F),
functional channels with different properties were obtained. WT BNaC-2
resided in a closed state with short openings, whereas GF BNaC-2 was
constitutively activated; a decrease in the pH in the trans
compartment of the bilayer activated WT BNaC-2 and decreased its
permeability for Na+ over K+. Moreover, these
maneuvers made the WT channel more resistant to amiloride. In contrast,
GF BNaC-2 did not respond to a decrease in pH, and its amiloride
sensitivity and selectivity for Na+ over K+
were unaffected by this pH change. Buffering the bathing solutions with
EGTA to reduce the free [Ca2+] to <10 nM
increased WT single channel open probability 10-fold, but not that of
GF BNaC-2. Ca2+ blocked both WT and GF BNaC-2 in a dose-
and voltage-dependent fashion; single channel conductances
were unchanged. A drop in pH reduced the ability of Ca2+ to
inhibit these channels. These results show that BNaC-2 is an
amiloride-sensitive sodium channel and suggest that pH activation of
these channels could be, in part, a consequence of H+
"interference" with channel regulation by
Ca2+.
pH Alterations "Reset" Ca2+ Sensitivity of Brain
Na+ Channel 2, a Degenerin/Epithelial Na+ Ion
Channel, in Planar Lipid Bilayers*
,
,, and**
Physiology and Biophysics and
¶ Surgery, University of Alabama at Birmingham, Birmingham,
Alabama 35294-0005 and the § Department of Neurosurgery,
Emory University, Atlanta, Georgia 30322
*
This work was supported by National Institutes of Health
Grants DK 37206 and DK 56095.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.
Present address: ResGen, Huntsville, AL 35801.
**
To whom correspondence should be addressed: Dept. of Physiology and
Biophysics, University of Alabama at Birmingham, 1918 University Blvd.,
MCLM 704, Birmingham, AL 35294-0005. Tel.: 205-934-6220; Fax:
205-934-2377; E-mail: benos@physiology.uab.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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