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 receptorspecific 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␦-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.The maintenance of the three-dimensional architecture of the mammalian uterus is carefully regulated during pregnancy and after parturition. Production of fibrillar collagens (Types I and III) is up-regulated 10-fold in the uterus during pregnancy (1, 2). These collagens possess a rigid superhelical structure, which is responsible for providing the tensile strength necessary to accommodate the force exerted by the growing fetus. After parturition, a precisely programmed non-necrotic and non-inflammatory process of connective tissue remodeling occurs, which results in the rapid and dramatic degradation of the collagen amassed and returns the uterus to reproductive competence (3). This transition is initiated by the enzyme interstitial collagenase (matrix metalloproteinase-13; MMP-13), 1 a member of the matrix metalloproteinase family. It acts as not only the rate-limiting step but also the committed step in the catalysis of the degradation of extracellular collagen (4, 5). The expression of MMP-13 occurs during postpartum involution and is not present either during the pregnancy or even within hours prior to parturition. The myometrial smooth muscle cell of the uterus has been identified not only as the source for MMP-13 (6) but also that of its natural substrate, collagen (7). Thus, the myometrial smooth muscle...

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