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J. Biol. Chem., Vol. 276, Issue 21, 18423-18429, May 25, 2001
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From the Department of Cell Biology, Emory University School of
Medicine, Atlanta, Georgia 30322-3030
We examined the voltage-dependent
block of Ca2+-activated Cl
Functional Geometry of the Permeation Pathway of
Ca2+-activated Cl
Channels Inferred from
Analysis of Voltage-dependent Block*
channels by
anthacene-9-carboxylic acid (A9C), diphenylamine-2-carboxylic acid
(DPC), 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), and
niflumic acid (NFA) in excised inside-out and outside-out patches from
Xenopus oocytes. The fraction of the voltage field (
)
experienced by the blocking drug was determined from the voltage dependence of block. All the drugs blocked by entering the channel from
the outside. was 0.6 for A9C, 0.3 for DPC and DIDS, and <0.1 for
NFA. Because the voltage dependence of the drugs differed, the order of
potency was also voltage-dependent. At +100 mV the order of
potency was NFA > A9C > DIDS > DPC
(Ki (µM) = 10.1, 18.3, 48, and
111, respectively). Because the drugs are hydrophobic, they can cross
the bilayer when applied from the inside and block the channel from the
outside. The equilibrium geometries of the blockers were determined by
molecular modeling and compared with their blocking positions ().
This analysis suggests that the channel is an elliptical cone with the
largest opening facing the extracellular space. The selectivity filter has an apparent size of 0.33 × 0.75 nm, because
C(CN)3, which has these dimensions,
permeates. The external opening is at least 0.60 × 0.94 nm,
because DPC has these dimensions and penetrates the channel
~30%.
*
This work was supported by National Institutes of Health
Grant GM 60448.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. Tel.: 404-727-0444;
Fax: 404-727-6256; E-mail: criss@cellbio.emory.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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