Serotonin-induced MMP-13 production is mediated via phospholipase C, protein kinase C, and ERK1/2 in rat uterine smooth muscle cells.
Serotonin (5-hydroxytryptamine; 5-HT), acting via the 5-HT(2A) 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-HT(2A) receptor-specific antagonists ketanserin and spiperone. The phospholipase C (PLC) inhibitors 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 PKCdelta-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-HT(2A) 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.
Shum
Jenny K S
JK
Centers for Cell Biology and Cancer Research and Immunology and Microbial Disease, MC-151, Albany Medical College, Albany, New York 12208, USA.
Melendez
J Andres
JA
Jeffrey
John J
JJ
D000818:Animals; D002478:Cells, Cultured; D017364:Collagenases / Q000096:biosynthesis*; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D005260:Female; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D053509:Matrix Metalloproteinase 13; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009130:Muscle, Smooth / Q000166:cytology / Q000201:enzymology; D009215:Myometrium / Q000166:cytology / Q000201:enzymology*; D011494:Protein Kinases / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000378:metabolism*
D004791:Enzyme Inhibitors; D004963:Estrenes; D007527:Isoenzymes; D011760:Pyrrolidinones; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C074854:U 73343; D012701:Serotonin; D011494:Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat