Inducible Nitric-oxide Synthase Attenuates
Vasopressin-dependent Ca2+ Signaling in Rat
Hepatocytes*
Sandip
Patel
§,
Lawrence D.
Gaspers¶,
Sylviane
Boucherie
,
Elisabeth
Memin¶,
Kerri Anne
Stellato¶,
Gilles
Guillon**,
Laurent
Combettes, and
Andrew
P.
Thomas¶
From the Department of Physiology, University College
London, Gower Street, London WC1E 6BT, United Kingdom, the
¶ Department of Pharmacology and Physiology, University of
Medicine and Dentistry of New Jersey, Newark, New Jersey 07103, Unite de Recherche U422, INSERM, Universite Paris Sud, 443, 91405 Orsay, France, and the ** Unite de Recherche U469,
Centre CNRS-INSERM de Pharmacologie Endocrinologie,
34094 Montpellier, France
Increases in both Ca2+ and
nitric oxide levels are vital for a variety of cellular processes;
however, the interaction between these two crucial messengers is not
fully understood. Here, we demonstrate that expression of inducible
nitric-oxide synthase in hepatocytes, in response to inflammatory
mediators, dramatically attenuates Ca2+ signaling by the
inositol 1,4,5-trisphosphate-forming hormone, vasopressin. The
inhibitory effects of induction were reversed by nitric oxide
inhibitors and mimicked by prolonged cyclic GMP elevation. Induction
was without effect on Ca2+ signals in response to
AlF
or inositol 1,4,5-trisphosphate, indicating that
phospholipase C activation and release of Ca2+ from
inositol 1,4,5-trisphosphate-sensitive Ca2+ stores were not
targets for nitric oxide inhibition. Vasopressin receptor levels,
however, were dramatically reduced in induced cultures. Our data
provide a possible mechanism for hepatocyte dysfunction during chronic inflammation.
*
This work was supported in part by a grant from the
Foundation of the University of Medicine and Dentistry of New Jersey
(to L. D. G.), by Grant Association pour la Recherche sur le
Cancer 5457 (to L. C.), and by National Institutes of
Health Grant DK38422 (to A. P. T.).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.
§
Recipient of a Wellcome Trust Research Career Development
Fellowship. To whom correspondence should be addressed. Tel.:
44-207-679-6540; Fax: 44-207-387-6368; E-mail:
patel.s@ucl.ac.uk.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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