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J. Biol. Chem., Vol. 277, Issue 20, 17758-17764, May 17, 2002
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From the Membrane guanylate cyclase C (GC-C) is the
receptor for guanylin, uroguanylin, and heat-stable enterotoxin (STa)
in the intestine. GC-C-deficient mice show resistance to STa in
intestine but saluretic and diuretic effects of uroguanylin and STa are
not disturbed. Here we describe the cellular effects of these peptides
using immortalized human kidney epithelial (IHKE-1) cells with
properties of the proximal tubule, analyzed with the slow-whole-cell
patch clamp technique. Uroguanylin (10 or 100 nM)
either hyperpolarized or depolarized membrane voltages (Vm).
Guanylin and STa (both 10 or 100 nM), as well as 8-Br-cGMP
(100 µM), depolarized Vm. All peptide effects
were absent in the presence of 1 mM Ba2+.
Uroguanylin and guanylin changed Vm pH dependently. Pertussis
toxin (1 µg/ml, 24 h) inhibited hyperpolarizations caused by uroguanylin. Depolarizations caused by guanylin and uroguanylin were
blocked by the tyrosine kinase inhibitor, genistein (10 µM). All three peptides increased cellular cGMP. mRNA
for GC-C was detected in IHKE-1 cells and in isolated human proximal
tubules. In IHKE-1 cells GC-C was also detected by immunostaining.
These findings suggest that GC-C is probably the receptor for guanylin and STa. For uroguanylin two distinct signaling pathways exist in
IHKE-1 cells, one involves GC-C and cGMP as second messenger, the other
is cGMP-independent and connected to a pertussis toxin-sensitive G protein.
Guanylin, Uroguanylin, and Heat-stable Euterotoxin Activate
Guanylate Cyclase C and/or a Pertussis Toxin-sensitive G
Protein in Human Proximal Tubule Cells*
e
,
oglu,,,
Medizinische Klinik und Poliklinik D,
Experimentelle Nephrologie, Universitätsklinikum
Münster, Domagkstr. 3a, D-48149 Münster, Germany, the
§ Institut für Pharmakologie und Toxikologie,
Universitätsklinikum Münster, Domagkstr. 12, D-48149
Münster, Germany, and the ¶ Department of Molecular
Reproduction, Development and Genetics, Indian Institut of Science,
Bangalore 560012, India
*
This work was supported by Deutsche Forschungsgemeinschaft
Grants Schl 277/5-5 to 5-6 and Innovative Medizinische Forschung of the
Medical Faculty of the University of Münster Grant KU 21 98 09.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:
Universitätsklinikum Münster, Medizinische Klinik und
Poliklinik D, Experimentelle Nephrologie, Domagkstr. 3a, D-48149
Münster, Germany. Tel.: 49-251-83-56991; Fax: 49-251-83-56973;
E-mail: eberhard.schlatter@ uni-muenster.de.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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