Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Detailed endocrinological studies were performed in the three affected kindred of a family carrying mutations of the GnRH receptor gene. All three were compound heterozygotes carrying on one allele the Arg262Gln mutation and on the other allele two mutations (Gln106Arg and Ser217Arg). When expressed in heterologous cells, both Gln106Arg and Ser217Arg mutations altered hormone binding, whereas the Arg262Gln mutation altered activation of phospholipase C. The propositus, a 30-yr-old man, displayed complete idiopathic hypogonadotropic hypogonadism with extremely low plasma levels of gonadotropins, absence of pulsatility of endogenous LH and alpha-subunit, absence of response to GnRH and GnRH agonist (triptorelin), and absence of effect of pulsatile administration of GnRH. The two sisters, 24 and 18 yr old, of the propositus displayed, on the contrary, only partial idiopathic hypogonadotropic hypogonadism. They both had primary amenorrhea, and the younger sister displayed retarded bone maturation and uterus development, but both sisters had normal breast development. Gonadotropin concentrations were normal or low, but in both cases were restored to normal levels by a single injection of GnRH. In the two sisters, there were no spontaneous pulses of LH, but pulsatile administration of GnRH provoked a pulsatile secretion of LH in the younger sister. The same mutations of the GnRH receptor gene may thus determine different degrees of alteration of gonadotropin function in affected kindred of the same family.
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PMID:The same molecular defects of the gonadotropin-releasing hormone receptor determine a variable degree of hypogonadism in affected kindred. 1002 17

The polychlorinated biphenyl (PCB) mixture Aroclor 1242 (A1242) increases frequency of contractions of pregnant rat uteri, suggesting a possible mechanism for decreased gestational age and increased spontaneous abortion in women and animals exposed to PCBs. In the present study, we hypothesized that A1242-induced stimulation of uterine contraction is mediated by arachidonic acid released by phospholipase A2 (PLA2) enzymes. Isometric uterine contraction was measured in longitudinal uterine strips isolated from gestation day 10 rat. Pretreatment of uterine strips with the PLA2 inhibitor (E)-6-(bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one (HELSS) or manoalide, or an inhibitor of the G protein of PLA2, isotetrandrine, completely prevented the increase of contractile frequency induced by 50 microM A1242. However, the phospholipase C inhibitors 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (NCDC) and neomycin were unable to block stimulation of uterine contraction by A1242. In accordance, A1242 (100 microM) did not release inositol phosphates from myo-[3H]inositol-labeled myometrial cells, whereas myometrial cells prelabeled with [3H]arachidonic acid released arachidonic acid in a concentration- and time-dependent manner after exposure to A1242 (10-100 microM). A1242 significantly stimulated arachidonic acid release in the absence of extracellular calcium, although the release was attenuated. Analysis of the eicosanoids released by A1242 indicated that only 0.83% of released [3H]arachidonic acid was metabolized to eicosanoids and 99.07% remained as free arachidonate. Uterine contraction increased in strips exposed to exogenous arachidonic acid (1-100 microM). This study suggests that A1242 stimulates contraction in pregnant rat uterus by a mechanism involving PLA2-mediated arachidonic acid release, and that arachidonic acid, rather than eicosanoids, may mediate A1242 uterotonic action in the uterus.
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PMID:Stimulation of pregnant rat uterine contraction by the polychlorinated biphenyl (PCB) mixture aroclor 1242 may be mediated by arachidonic acid release through activation of phospholipase A2 enzymes. 1021 94

The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation. Such stimuli also lead to an intranuclear release of OT. Moreover, oxytocinergic neurons display widespread projections throughout the central nervous system. However, OT is also synthesized in peripheral tissues, e.g., uterus, placenta, amnion, corpus luteum, testis, and heart. The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via G(q) proteins to phospholipase C-beta. The high-affinity receptor state requires both Mg(2+) and cholesterol, which probably function as allosteric modulators. The agonist-binding region of the receptor has been characterized by mutagenesis and molecular modeling and is different from the antagonist binding site. The function and physiological regulation of the OT system is strongly steroid dependent. However, this is, unexpectedly, only partially reflected by the promoter sequences in the OT receptor gene. The classical actions of OT are stimulation of uterine smooth muscle contraction during labor and milk ejection during lactation. While the essential role of OT for the milk let-down reflex has been confirmed in OT-deficient mice, OT's role in parturition is obviously more complex. Before the onset of labor, uterine sensitivity to OT markedly increases concomitant with a strong upregulation of OT receptors in the myometrium and, to a lesser extent, in the decidua where OT stimulates the release of PGF(2 alpha). Experiments with transgenic mice suggest that OT acts as a luteotrophic hormone opposing the luteolytic action of PGF(2 alpha). Thus, to initiate labor, it might be essential to generate sufficient PGF(2 alpha) to overcome the luteotrophic action of OT in late gestation. OT also plays an important role in many other reproduction-related functions, such as control of the estrous cycle length, follicle luteinization in the ovary, and ovarian steroidogenesis. In the male, OT is a potent stimulator of spontaneous erections in rats and is involved in ejaculation. OT receptors have also been identified in other tissues, including the kidney, heart, thymus, pancreas, and adipocytes. For example, in the rat, OT is a cardiovascular hormone acting in concert with atrial natriuretic peptide to induce natriuresis and kaliuresis. The central actions of OT range from the modulation of the neuroendocrine reflexes to the establishment of complex social and bonding behaviors related to the reproduction and care of the offspring. OT exerts potent antistress effects that may facilitate pair bonds. Overall, the regulation by gonadal and adrenal steroids is one of the most remarkable features of the OT system and is, unfortunately, the least understood. One has to conclude that the physiological regulation of the OT system will remain puzzling as long as the molecular mechanisms of genomic and nongenomic actions of steroids have not been clarified.
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PMID:The oxytocin receptor system: structure, function, and regulation. 1127 41

Oxytocin and vasopressin are related peptides that have receptors in the uterus. Species from families other than Suidae produce only arginine-vasopressin; in contrast, pigs apparently express both arginine- and lysine-vasopressin. The aim of this study was to determine whether arginine- or lysine-vasopressin would activate phospholipase C, increase intracellular calcium concentration [Ca(2+)](i) and stimulate PGF(2alpha) production in enriched cultures of stromal, glandular epithelial and luminal epithelial cells from pig endometrium. Cells were obtained from gilts on day 16 after oestrus by differential enzymatic digestion and sieve separation. After 96 h in culture, the cells were treated with 0 or 100 nmol arginine- or lysine-vasopressin l(-1). The responses to 100 nmol oxytocin l(-1) and 100 nmol GnRH l(-1) were used as positive and negative controls, respectively. Consistent with previous results, oxytocin stimulated phospholipase C activity (P < 0.05), increased [Ca(2+)](i) (P < 0.05) and promoted PGF(2alpha) secretion (P < 0.05) from stromal and glandular epithelial cells. Activity of phospholipase C, [Ca(2+)](i) and PGF(2alpha) release were also increased (P < 0.05) by arginine-vasopressin in stromal cells, but the responses were less (P < 0.01) than those induced by oxytocin. An oxytocin antagonist attenuated the [Ca(2+)](i) response of stromal cells to both oxytocin and arginine-vasopressin. Sequential treatment of cells with oxytocin and arginine-vasopressin indicated that oxytocin desensitized the response to oxytocin, but arginine-vasopressin did not similarly desensitize the response to oxytocin. In glandular and luminal epithelial cells, arginine-vasopressin did not stimulate phospholipase C activity, [Ca(2+)](i) or PGF(2alpha) secretion. Neither GnRH nor lysine-vasopressin induced phospholipase C activity, increased [Ca(2+)](i) or stimulated PGF(2alpha) production in any endometrial cell type. These results indicate that oxytocin receptors can bind arginine-vasopressin more readily than they bind lysine-vasopressin. Type 1 vasopressin receptors may also exist in endometrium predominantly on cells other than stromal, glandular epithelial and luminal epithelial cells, as in previous studies both arginine-vasopressin and lysine-vasopressin stimulated phospholipase C activity in endometrial explants to a similar extent as oxytocin.
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PMID:Effects of arginine- and lysine-vasopressin on phospholipase C activity, intracellular calcium concentration and prostaglandin F2alpha secretion in pig endometrial cells. 1127 81

Binding sites for LH/hCG are found in the uterus of several species, including humans. In cattle and pigs, the LH receptor, its mRNA and LH receptor protein are present in the uterus throughout the oestrous cycle, and maximum expression occurs at the luteal phase. GnRH receptor is also expressed maximally in the human endometrium at the luteal phase. LH activates both the adenylate cyclase and phospholipase C pathways and increases the concentrations of cyclooxygenase and its products. Activation of LH receptors in the endometrium is associated with PGF production. In contrast, bovine uterine vein LH receptor mRNA and LH receptor concentrations are greatest during pro-oestrus-oestrus and LH increases the production of both PGE and PGF. FSH receptor and its mRNA are present in the bovine cervix and the concentrations are greatest at the time of the FSH peak value in the blood, indicating a physiological role for FSH in the relaxation and opening of the cervix. The presence of gonadotrophin and releasing factor receptors with a dynamic pattern in the endometrium, myometrium, oviduct and cervix of different species provides evidence that gonadotrophins and GnRH play a substantial role as molecular autocrine-paracrine regulators of the oestrous cycle and implantation.
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PMID:Actions of gonadotrophins on the uterus. 1137 69

Bovine myometrium and cervix contain luteinizing hormone/human chorionic gonadotropin (LH/hCG) binding sites, LH receptor (LH-R) messenger RNA (mRNA), and LH-R protein. Expression of LH-R is dependent on the stage of the cycle. LH-R expression is high during the luteal phase but weak during the follicular phase. In both myometrium and cervix, LH activates both the adenylate cyclase and phospholipase C pathways, and the effect of LH on both pathways at each stage of the cycle is correlated with the amount of LH-R present in the tissue. Because activation of cyclic AMP (cAMP) is associated with myometrial quiescence, we suggest that LH activation of uterine cAMP could serve to keep the uterus quiescent during the luteal phase. On the other hand, in the uterine vein LH-R mRNA and LH-R are maximal during preestrus/estrus as opposed to the luteal phase. In the uterine vein, LH increases the expression of cyclooxygenase and production of both prostaglandin E2 (PGE2) and PGF2 alpha. Because PGF2 alpha is the physiological luteolytic signal in the cow, we suggest that this increase in prostaglandin production by the uterine vein is part of the physiological events leading to luteolysis. In addition to uterine LH-R, the bovine cervix at preestrus/estrus has high levels of follicle-stimulating hormone receptor (FSH-R) and its corresponding mRNA. As with LH-R, activation of FSH-R by FSH is associated with activation of a G protein-coupled receptor family that mediates the cAMP and inositol phosphate signaling pathways. Activation of these signaling pathways is associated with an increase in the expression of cyclooxygenase and production of PGE2. Because expression of the FSH receptor was maximal at the time of the FSH peak in the blood, we suggest a physiological role for FSH in the cervix relaxation and opening at estrus.
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PMID:Functional importance of bovine myometrial and vascular LH receptors and cervical FSH receptors. 1139 9

Although regulation of uterine contractility is fundamental for parturition, mechanisms by which toxicants modify uterine muscle contractions remain poorly understood. In a previous cumulative concentration-response study, 10 microM lindane (gamma-hexachlorocyclohexane) reduced contraction force and 30 microM lindane abolished contractions in Gestation Day 10 rat uterine strips when lindane was added to muscle baths at 10-min intervals. Other studies showed that brief (<10 min) exposures to 10-100 microM lindane inhibit gap junctions and activate phospholipase pathways in rat myometrial cells in culture. Consequently, lindane was used as a prototype toxicant with known uterine activity to investigate the hypothesis that activation of a specific phospholipase pathway provides a mechanistic link between inhibition of uterine contraction and inhibition of myometrial gap junctions. Uterine tissue and cells were pretreated with phospholipase pathway inhibitors to evaluate the role of phospholipase pathways in lindane's actions in the uterus. Concentrations of inhibitors were selected based on previous reports of effective concentrations for the enzyme activity and on pilot toxicity studies of the inhibitors on uterine contraction and gap junction communication. To monitor uterine contractions, longitudinal uterine strips were excised from Gestation Day 10 rats and suspended in isometric muscle baths, consistent with previous experiments. Exposure in vitro for 60 min to 10-50 microM lindane, an effective concentration range for the uterine responses of interest, revealed that 30 microM lindane rapidly abolished contractions. Subsequently, uterine strips were pretreated with phospholipase pathway inhibitors and then challenged with 30 microM lindane, the lindane concentration that elicited maximal inhibition of uterine contraction. Pretreatment with 20-50 microM of the phosphatidylinositol-specific phospholipase C inhibitor 1-O-octadecyl-2-O-methyl-sn-glycerol-3-phosphorylcholine (ET-18-OCH(3)) reversed lindane-induced inhibition of spontaneous uterine contractions. Gap junction intercellular communication was monitored by injecting the fluorescent dye Lucifer yellow into rat myometrial cells grown in culture and assessing dye transfer to adjacent cells using epifluorescence microscopy. Similar to uterine contraction, pretreatment of cell cultures with phospholipase C inhibitors (30 microM ET-18-OCH(3), 50 microM tricyclodecan-p-yl-xanthogenate.K [D609] or 50 microM tricyclodecan-p-yl-xanthogenate.K or 2-nitro-4-carboxyphenyl-N,N-dophenylcarbamate [NCDC]) partially reversed inhibition of dye transfer by 100 microM lindane, a lindane concentration previously shown to abolish myometrial Lucifer yellow dye transfer under similar culture conditions. In contrast, pretreatment with 20 microM of bromoenol lactone (BEL) to inhibit the calcium-independent phospholipase A(2) or 100 mM ethanol to interrupt the phospholipase D pathway failed to prevent inhibition of spontaneous uterine contractions and inhibition of Lucifer yellow dye transfer by lindane (100 microM). These data suggest that lindane inhibits myometrial gap junctions and spontaneous oscillatory contractions by a phospholipase C-mediated pathway.
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PMID:Phospholipase-mediated inhibition of spontaneous oscillatory uterine contractions by lindane in vitro. 1214 Jan 77

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.
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PMID:Serotonin-induced MMP-13 production is mediated via phospholipase C, protein kinase C, and ERK1/2 in rat uterine smooth muscle cells. 1221 12

Although the presence of endometrial receptors for angiotensin (Ang) II has been demonstrated, a specific function for AngII in the uterus has not been identified. Cytosolic free Ca2+ concentration [Ca2+]i, phospholipase C (PLC) activity and prostaglandin (PG) F2alpha secretion in response to AngII and oxytocin (OT) were measured in pig endometrial stromal cells collected 16 days after oestrus. Treatment with 100 nM OT or AngII increased (P<0.001) [Ca2+]i in stromal cells similarly (720 +/- 34 v. 690 +/- 33 pM, respectively). Subsequent administration of OT or AngII to the same cells induced smaller [Ca2+]i increases (25% or 35% of the initial responses, respectively) that occurred only if the second exposure to the same agent took place at least 5 min after the first. When administered sequentially, OT and AngII each induced a full response within 1 min of the previous treatment, regardless of which peptide was applied first. Whereas OT increased PLC activity and PGF2alpha secretion in stromal cells (P<0.01), AngII did not increase either PLC activity or PGF2alpha secretion. Type I AngII (AT1) receptors were present on stromal cells, whereas AT2 receptors were absent. Therefore, the effect of AngII in stromal cells was mediated via AT1 receptors. That AngII increased [Ca2+]i in stromal cells, but did not increase PLC or PGF2alpha secretion, indicates that either AngII releases a pool of Ca2+ through a mechanism that is not mediated by PLC and is not involved in PGF2alpha secretion or that a mechanism for PGF2alpha production other than one involving Ca2+ may exist.
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PMID:Angiotensin II increases intracellular calcium concentration in pig endometrial stromal cells through type 1 angiotensin receptors, but does not stimulate phospholipase C activity or prostaglandin F2alpha secretion. 1221 42

A highly proliferative, migratory and invasive subpopulation of human placental trophoblasts, known as extravillous trophoblasts (EVT), invades the uterus and its vasculature, to establish an adequate exchange of key molecules between the maternal and fetal circulation. Our earlier studies provided evidence for a positive regulation of migration/invasion of EVT by an autocrine factor IGFII and a paracrine, decidua-derived factor IGFBP1. The present study examined the role played by endothelin (ET)-1, also produced at the fetal-maternal interface, and its receptor subtypes ET(A) and ET(B) in the regulation of human EVT cell functions. We utilized an in vitro propagated EVT cell line (HTR-8/SVneo) which exhibits the phenotypic and functional characteristics of EVT in situ. Reverse transcription-PCR with primers specific for prepro-ET-1, ET(A) and ET(B) cDNAs demonstrated the expression of all these genes in HTR-8/SVneo cells. While proliferation was not influenced, migration of these cells through porous Transwell membranes was stimulated by exogenous ET-1. ET-1 also induced biphasic elevation of cytosolic free Ca(2+) concentrations ([Ca(2+)](i)) consisting of an initial transient followed by a sustained plateau, as measured by spectrofluorimetry. The dependence of the Ca(2+) response on phospholipase C (PLC) was demonstrated by its abrogation in the presence of PLC inhibitor U73122. Furthermore, ET-1 treatment of EVT cells rapidly stimulated phosphorylation of MAP kinase (ERK1/2). By using ET receptor antagonists and agonists, it was shown that both ET(A) and ET(B) receptors were responsible for the effects of ET-1 on migration, [Ca(2+)](i) and MAPK phosphorylation. Thus, ET-1 may represent an autocrine/paracrine mediator of invasive trophoblast function.
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PMID:Endothelin-1 promotes migration and induces elevation of [Ca2+]i and phosphorylation of MAP kinase of a human extravillous trophoblast cell line. 1270 95


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