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J. Biol. Chem., Vol. 277, Issue 45, 42830-42840, November 8, 2002
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From the Centers for Serotonin (5-hydroxytryptamine; 5-HT), acting via
the 5-HT2A receptor, up-regulates the transcription
and production of interstitial collagenase (matrix
metalloproteinase-13; MMP-13), a critical enzyme responsible for
maintaining the integrity of the uterus, after parturition. Serotonin
treatment of rat uterine myometrial smooth muscle cells induced
inositol phosphate (IP) turnover, which was abolished by the
5-HT2A receptor-specific antagonists ketanserin and
spiperone. The phospholipase C (PLC) inhibitors U73122 and D609
attenuated serotonin-mediated-IP turnover with a corresponding
inhibition of MMP-13 protein production. Subsequent recovery of both
MMP-13 protein expression and IP generation was seen following the
removal of D609. Protein kinase C (PKC) activators, the diacylglycerol
analogue 1,2-dioctanoyl-sn-glycerol and phorbol myristate
acetate (PMA), mimicked the effect of serotonin on MMP-13 protein
expression; prolonged PMA treatment (which down-regulates PKC)
lowered MMP-13 protein levels. The PKC-specific inhibitors bisindolylmaleimide I, calphostin C, CGP 41251, and the
PKC
Serotonin-induced MMP-13 Production Is Mediated via Phospholipase
C, Protein Kinase C, and ERK1/2 in Rat Uterine Smooth Muscle
Cells*
,
, and
Cell Biology and Cancer Research
and § Immunology and Microbial Disease, MC-151, Albany
Medical College, Albany, New York 12208
-selective inhibitor rottlerin were able to suppress serotonin
up-regulation of MMP-13. Furthermore, the mitogen-activated protein
kinase kinase (MEK) inhibitor PD98059 blocked
serotonin-dependent activation of p44/42 MAPK (pERK1/2), a
downstream effector of PKC and also down-regulated MMP-13 protein
expression. Similarly, calphostin C and rottlerin depressed activation
of p44/42 MAPK. From these studies, serotonin, binding through the
5-HT2A receptor, initiates a signaling cascade whereby
stimulation of PLC leads to the activation of PKC and
subsequently the ERK1/2 pathway, which ultimately results in MMP-13 production.
*
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.:
518-262-8791; Fax: 518-262-6161; E-mail: melenda@mail.amc.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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