Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously reported that kappa opiates stimulated the release of human placental lactogen (hPL) from human placental cells. In this study, we investigated the role of adenylate cyclase as a potential cellular mediator of such an effect. Incubations with ethylketocyclazocine (EKC) led to a time- and dose-dependent inhibition of adenylate cyclase activity. The maximal inhibition was 45 +/- 5% of control value after 15 min exposure to 10(-7)M EKC. This inhibition was reversed by opiate antagonist naloxone and was specific to kappa opiate type. Preincubation of human trophoblastic cells with 0.1 microgram/ml Islet-Activating-Protein (IAP; also called pertussis toxin) did not modify basal adenylate cyclase activity but abolished the inhibition of adenylate cyclase activity by EKC, indicating that the effect of opiates on cAMP production was mediated by an IAP-sensitive GTP binding protein. Also, IAP stimulated basal hPL release; the control levels were 22.4 ng/ml and 46.5 ng/ml without and with IAP respectively. However, the EKC-stimulated hPL levels were unchanged by preincubation with IAP. This difference in cAMP and hPL response in IAP-treated cells suggested that the opiate receptors are not directly coupled to adenylate cyclase. This hypothesis was confirmed by 1) experiments on placental membranes showing that in absence of the cytoplasmic elements (membranes only), EKC had no effect on membrane adenylate cyclase and 2) experiments on placental cells showing that dibutyryl-cAMP (dbcAMP) stimulated hPL release.
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PMID:Adenosine 3':5'-cyclic monophosphate (cAMP) is not the mediator of kappa opiate effect on human placental lactogen release. 165 Aug 74

We previously reported that kappa opioids stimulated the release of human placental lactogen (hPL) from trophoblastic cells and that this effect was prevented by co-incubation with naloxone. We also reported that adenylate cyclase was not directly involved in this process. In order to understand the post-receptor events mediating hPL release by opioids in the human placenta, we studied the role of extracellular calcium. Human trophoblastic cells obtained by trypsin digestion were cultured for 48 h in Ham's F-10 medium supplemented with 10% fetal bovine serum (FBS), 200 U/ml penicillin, and 200 micrograms/ml streptomycin. 45Ca2+ influx was then measured by filtration on glass-fiber filters. We observed a time- and dose-dependent stimulation of 45Ca2+ influx by ethylketocyclazocine (EKC) with an EC50 of 0.5 nM and a maximal stimulation of 196% over control. This effect was completely blocked by naloxone, a non-specific opioid antagonist, and by nor-binaltorphimine, a specific kappa antagonist. We also demonstrated that U-50,488 (kappa agonist) had the same stimulatory effect as EKC (221 +/- 25% of control). D-Ala2,NMe-Phe4,Gly-ol5)-enkephalin (DAGO) (mu agonist) slightly stimulated Ca2+ influx (128 +/- 5% of control, p > 0.05) whereas D-Ser2,Leu,Thr6)-enkephalin (DSLET) (delta agonist) had no effect. Pre-incubation of trophoblastic cells with pertussis toxin (PTX) did not affect the EKC-induced 45Ca2+ influx, suggesting that this placental opiate effect is not coupled with PTX-sensitive G proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The modulation of placental lactogen release by opioids: a role for extracellular calcium. 768 40

We previously reported that angiotensin-II (AII) stimulated and dopamine (DA) inhibited the release of human placental lactogen (hPL) from trophoblastic cells. The mechanisms of action involved in these endocrine regulations are poorly known. In this study, we investigated the role of Ca2+ as a potential cellular mediator of the effects of AII and DA. Incubation of freshly isolated human term trophoblastic cells with DA led to a dose-dependent inhibition of 45Ca2+ influx, with a maximum of 55 +/- 5% and an EC50 of 10 +/- 3 mumol/L. This DA-inhibited Ca2+ influx was reversed by spiperone, a D2-dopamine receptor antagonist. Preincubation of cells with pertussis toxin completely blocked the inhibitory effect of DA on placental 45Ca2+ influx. Nifedipine (10(-5) mol/L), like DA, inhibited 45Ca2+ influx (41 +/- 3% inhibition). Moreover, nifedipine decreased hPL release (57 +/- 10%; EC50, 0.25 +/- 0.09 mumol/L). Coincubation of DA and nifedipine did not enhance the inhibitory effects of these agents on either 45Ca2+ influx or hPL release. The incubation of trophoblastic cells with [Sar1]AII, a potent agonist of AII, led to a dose-dependent stimulation of 45Ca2+ influx. The maximal stimulation was 221 +/- 37% of the control value, with an EC50 of 50 +/- 15 nmol/L. This stimulation was inhibited by coincubation with the AII antagonist [Sar1,Ala8]AII. [Sar1]AII-stimulated Ca2+ influx was blocked by preincubation with pertussis toxin. Bay K 8644 also stimulated 45Ca2+ influx (238 +/- 41% of the control). Moreover, Bay K 8644 stimulated hPL release. The maximal stimulation was 180 +/- 22% of the control value, with an EC50 of 0.40 +/- 0.30 mumol/L. Coincubation of Bay K 8644 and AII did not led to additional stimulation of either 45Ca2+ influx or hPL release. These results suggest that Ca2+ influx is one mechanism that mediates AII and DA regulation of hPL release in human term trophoblastic cells.
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PMID:A role for extracellular calcium in the regulation of placental lactogen release by angiotensin-II and dopamine in human term trophoblastic cells. 769 Mar 61

Recent data suggest an important role for calcium (Ca2+) in human placental endocrinology. Thus, the regulation of Ca2+ influx seems to be implicated in the modulation of human placental lactogen and hCG release. A possible mechanism of influx regulation is through receptor-operated channels. One of the most characterized receptor gating Ca2+ channels, the ATP receptor, stimulates the intracellular calcium concentration ([Ca2+]i) in various tissues. The aim of this study was to determine whether ATP receptors gating Ca2+ channels are also present in placental cells. We thus determined the effect of ATP on [Ca2+]i in human term trophoblastic cells loaded with the Ca(2+)-responsive fluorescent dye fura-2. ATP stimulated a 4.3 +/- 0.4 (+/- SE)-fold increase in [Ca2+]i, with a half-maximal effective concentration (EC50) of 1.5 mumol/L. The pharmacological activation profile suggests the presence of purinergic P2u receptors (nucleotide receptors), because uridine 5'-triphosphate (UTP) also stimulated [Ca2+]i (4.0-fold increase, with an EC50 of 10 mumol/L). The ATP-stimulated [Ca2+]i was partly sensitive to pertussis toxin; we observed a 58% inhibition of ATP-induced [Ca2+]i with the toxin without effect on basal [Ca2+]i. The ATP- and UTP-stimulated [Ca2+]i declined with time in the presence of ATP (or UTP). The rate of deactivation was rapid (t1/2, < 60 s with 10(-5) mol/L ATP) and concentration dependent. The deactivation occurring during one application of ATP or UTP resulted in a diminution of subsequent responses. The recovery was incomplete even with long waiting times (up to 30 min). ATP and UTP also stimulated inositol phosphate production with EC50 values of 11 and 15 mumol/L, respectively, but not human placental lactogen or hCG release in experiments in which known secretagogues were effective. The results suggest the presence in human term placental cells of P2u receptors pharmacologically similar to those observed in other tissues, especially in the pituitary and amnion. The physiological significance of this stimulation of [Ca2+]i by ATP and UTP in the human placenta remains to be investigated.
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PMID:Stimulation of intracellular calcium concentration by adenosine triphosphate and uridine 5'-triphosphate in human term placental cells: evidence for purinergic receptors. 777 28

To determine whether G proteins are involved in the regulation of mouse placental lactogen-I (mPL-I) and/or mPL-II secretion before midpregnancy, mouse placental tissue from day 7 of pregnancy was dispersed with collagenase, cells were fractionated on a percoll gradient, and the purified trophoblast cells were cultured in a serum-free medium with cholera toxin (CTX) or pertussis toxin (PTX) which modulate the activities of distinct G proteins for 5 days. CTX inhibited both mPL-I and mPL-II secretion, but PTX inhibited mPL-I secretion and stimulated mPL-II secretion in a time- and dose-dependent manner. Addition of both CTX and PTX additionally inhibited mPL-I secretion but did not affect mPL-II secretion. 8-Bromo cAMP, which increases intracellular cAMP accumulation, inhibited both mPL-I and mPL-II secretion similarly to CTX. In contrast, H8, an inhibitor of cAMP-dependent protein kinase A, stimulated both mPL-I and mPL-II secretion. Addition of PTX and H8 synergistically stimulated mPL-II secretion. These findings suggest that G proteins play important roles in regulation of mPL-I and mPL-II secretion before midpregnancy.
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PMID:Regulation of mouse placental lactogen secretion by G proteins before midpregnancy. 890 70

We have demonstrated the presence in human placenta of D2 dopamine receptors (D2R) which inhibit human placental lactogen (hPL) release. This inhibitory effect of dopamine (DA) was sensitive to pertussis toxin (PTX) indicating that it may be mediated by the Gi/Go family of G proteins. However, nothing is known on this G proteins/D2R interaction in human placenta. In this study, we demonstrate that DA (10(-4) M) inhibits by 39% the ADP-ribosylation by PTX of two G proteins of 40 and 41 kDa. This inhibition is receptor specific since it is reversed by spiperone, a D2R antagonist. Moreover we show that bromocriptine, a D2 agonist, inhibited the labeling of these two proteins in a dose-dependent manner with a maximal inhibition of 37% at a concentration of 10(-6) M. In order to understand the role of D2R in placental endocrinology, we have analyzed the interactions of these two PTX-sensitive G proteins with D2R in normal and abnormal pregnancies. The autoradiographs of both PTX ADP-ribosylated placental proteins of 40 and 41 kDa showed differential labeling during normal pregnancy. Thus, the relative levels of ADP-ribosylation by PTX of both proteins were 2.5 and 3.0 fold lower at term than those observed during first and second trimester whereas no difference was observed between the first and second trimester. Also, no significant change in the level of inhibition by DA was observed between 7-9 weeks and 18-40 weeks of pregnancies (35-45% inhibition). However, we observed a maximal inhibition between 10 to 17 weeks of pregnancy (64% inhibition). In placentas from preeclamptic pregnancies, the levels of ADP-ribosylation were similar to those observed in normal pregnancy, while the DA inhibition was increased by 24%. The levels of ADP-ribosylation in molar placentas reached 20% of normal values, while no difference in DA inhibition was observed. This study demonstrates that two distinct PTX-sensitive G proteins are coupled to human placental D2R. The physiological significance of the variations in these ADP-ribosylated-G proteins/D2R interaction during normal and preeclamptic pregnancies remains to be investigated.
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PMID:Interaction of D2-dopamine receptor with two pertussis toxin sensitive G proteins in human placenta. 909 57