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J. Biol. Chem., Vol. 276, Issue 23, 19729-19737, June 8, 2001
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From the Smooth Muscle Research Group, Department of Pharmacology
and Therapeutics, Faculty of Medicine, The University of Calgary,
Calgary, Alberta, Canada T2N 4N1
The activation of large conductance,
calcium-sensitive K+ (BKCa) channels by
the nitric oxide (NO)/cyclic GMP (cGMP) signaling pathway appears to be
an important cellular mechanism contributing to the relaxation of
smooth muscle. In HEK 293 cells transiently transfected with
BKCa channels, we observed that the NO donor sodium
nitroprusside and the membrane-permeable analog of cGMP, dibutyryl
cGMP, were both able to enhance BKCa channel activity 4-5-fold in cell-attached membrane patches. This enhancement
correlated with an endogenous cGMP-dependent protein kinase
activity and the presence of the
A Catalytically Inactive Mutant of Type I
cGMP-dependent Protein Kinase Prevents Enhancement of Large
Conductance, Calcium-sensitive K+ Channels by Sodium
Nitroprusside and cGMP*
and
isoform of type I
cGMP-dependent protein kinase (cGKI). We observed that
co-transfection of cells with BKCa channels and a
catalytically inactive ("dead") mutant of human cGKI prevented
enhancement of BKCa channel in response to either sodium
nitroprusside or dibutyryl cGMP in a dominant negative fashion. In
contrast, expression of wild-type cGKI supported enhancement of
channel activity by these two agents. Importantly, both endogenous and
expressed forms of cGKI were found to associate with
BKCa channel protein, as demonstrated by a reciprocal
co-immunoprecipitation strategy. In vitro, cGKI was able
to directly phosphorylate immunoprecipitated BKCa channels,
suggesting that cGKI-dependent phosphorylation of
BKCa channels in situ may be responsible for
the observed enhancement of channel activity. In summary, our data
demonstrate that cGKI alone is sufficient to promote the enhancement
of BKCa channels in situ after
activation of the NO/cGMP signaling pathway.
*
This study was supported by an Establishment Award from the
Alberta Heritage Foundation for Medical Research and a Medical Research
Council Operating Grant (to A. P. B.).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.
Supported by a Medical Research Council/Pharmaceutical
Manufacturers Association of Canada studentship award.
§
A Research Scholar of the Alberta Heritage Foundation for Medical
Research and the Heart and Stroke Foundation of Canada.
¶
To whom correspondence should be addressed: Dept. of
Pharmacology and Therapeutics, The University of Calgary, 3330 Hospital Dr., N.W., Calgary, Alberta, Canada T2N 4N1. Tel.: 403-220-8861; Fax:
403-270-2211; E-mail: abraun@ucalgary.ca
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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