Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The responsiveness of anterior pituitary tumor (GH3) cells to promoters of prolactin secretion and/or synthesis and cyclic AMP accumulation was studied as a function of cellular Ca2+ content. GH3 cells exposed to media containing 1 mM ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid were reduced 7-fold in Ca2+ content without loss of viability. Preparations of Ca2+-depleted cells were largely unchanged in cyclic AMP content when challenged by thyrotropin-releasing hormone (TRH), whereas cells which were subsequently restored at optimal Ca2+ (0.5 mM) responded to the hormone with 2- to 3-fold increases in cyclic AMP content. The decreased responsiveness of Ca2+-depleted cells to TRH was not influenced by phosphodiesterase inhibitors, incubation time, or hormone concentration. TRH-dependent cyclic AMP accumulation was markedly potentiated by forskolin in Ca2+-restored, but not in Ca2+-depleted, cell preparations. Forskolin extended the time period during which cyclic AMP accumulated in response to TRH without altering the TRH concentration dependency of the cells. Varying increases in GH3 cyclic AMP content occurred in response to other hormones or agents which enhance prolactin secretion and/or synthesis. In Ca2+-restored cells, cyclic AMP content was increased 2-fold by prostaglandin E1 (PGE1) and epidermal growth factor (EGF), 10- to 15-fold by vasoactive intestinal polypeptide (VIP) and 6-fold by phorbol myristate acetate (PMA); the capacity of Ca2+-depleted cells, however, to accumulate cyclic AMP in response to PGE1, EGF, and VIP was greatly reduced. Accumulation of cyclic AMP following short-term incubations with cholera toxin similarly was dependent on Ca2+. Exposure of GH3 cells preloaded with 45Ca to TRH, PGE1, EGF, PMA, or VIP resulted in losses of cell-associated 45Ca. Pretreatment with these agents resulted in a decreased capacity of the cells to accumulate 45Ca from the extracellular medium. The results of this study support the hypothesis that various putative humoral regulators of prolactin secretion and/or synthesis act on GH3 cells to alter intracellular Ca2+ metabolism which in turn results in an increased cyclic AMP content through stimulation of adenylate cyclase activity.
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PMID:Regulation of Ca2+-dependent cyclic AMP accumulation and Ca2+ metabolism in intact pituitary tumor cells by modulators of prolactin production. 630 Jun 49

Rat hepatocytes rapidly incorporate [32P]Pi into phosphatidylinositol 4-phosphate (PtdIns4P) and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2]; their monoester phosphate groups approach isotopic equilibrium with the cellular precursor pools within 1 h. Upon stimulation of these prelabelled cells with Ca2+-mobilizing stimuli (V1-vasopressin, angiotensin, alpha 1-adrenergic, ATP) there is a rapid fall in the labelling of PtdIns4P and PtdIns(4,5)P2. Pharmacological studies suggest that each of the four stimuli acts at a different population of receptors. Insulin, glucagon and prolactin do not provoke disappearance of labelled PtdIns4P and PtdIns(4,5)P2. The labelling of PtdIns4P and PtdIns(4,5)P2 in cells stimulated with vasopressin or angiotensin initially declines at a rate of 0.5-1.0% per s, reaches a minimum after 1-2 min and then returns towards the initial value. The dose-response curves for the vasopressin- and angiotensin-stimulated responses lie close to the respective receptor occupation curves, rather than at the lower hormone concentrations needed to evoke activation of glycogen phosphorylase. Disappearance of labelled PtdIns4P and PtdIns(4,5)P2 is not observed when cells are incubated with the ionophore A23187. The hormone-stimulated polyphosphoinositide disappearance is reduced, but not abolished, in Ca2+-depleted cells. These hormonal effects are not modified by 8-bromo cyclic GMP, cycloheximide or delta-hexachlorocyclohexane. The absolute rate of polyphosphoinositide breakdown in stimulated cells is similar to the rate previously reported for the disappearance of phosphatidylinositol [Kirk, Michell & Hems (1981) Biochem. J. 194, 155-165]. It seems likely that these changes in polyphosphoinositide labelling are caused by hormonal activation of the breakdown of PtdIns(4,5)P2 (and may be also PtdIns4P) by the action of a polyphosphoinositide phosphodiesterase. We therefore suggest that the initial response to hormones is breakdown of PtdIns(4,5)P2 (and PtdIns4P?), and that the simultaneous disappearance of phosphatidylinositol might be a result of its consumption for the continuing synthesis of polyphosphoinositides.
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PMID:Rapid breakdown of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate in rat hepatocytes stimulated by vasopressin and other Ca2+-mobilizing hormones. 630 53

Thyrotropin-releasing hormone (TRH; thyroliberin) stimulated rapid hydrolysis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] by a phosphodiesterase (phospholipase C) in GH3 cells, a prolactin-secreting rat pituitary tumour cell line. TRH caused a rapid decrease in the level of PtdIns(4,5)P2 to 60% of control and stimulated a marked transient increase in inositol 1,4,5-trisphosphate, the unique product of phosphodiesteratic hydrolysis of PtdIns(4,5)P2, to a peak of 410% of control at 15 s. TRH also caused decreases in phosphatidylinositol 4-monophosphate (PtdIns4P) and phosphatidylinositol (PtdIns) to 65% and 93% of control at 15 s respectively. Inositol 1,4-bisphosphate was increased to a peak of 450% at 30 s; inositol 1-monophosphate and inositol were not elevated until 30 s and 1 min respectively after TRH addition. To study whether PtdIns(4,5)P2 hydrolysis may be caused by an elevation in cytosolic Ca2+ concentration, the changes induced by TRH in the levels of inositol sugars were compared with the effects of membrane depolarization by high extracellular [K+]. The elevation in cytosolic [Ca2+] induced by K+ depolarization did not change the level of inositol 1,4,5-trisphosphate. These data suggest that phosphodiesteratic hydrolysis of PtdIns(4,5)P2 may be the initial event in TRH stimulation of inositol lipid metabolism in GH3 cells and that PtdIns(4,5)P2 hydrolysis is not stimulated by an elevation in cytosolic Ca2+ concentration. The decreases in PtdIns4P and PtdIns may be due to enhanced conversion of PtdIns into PtdIns4P into PtdIns(4,5)P2 or to their direct hydrolysis by phosphomonoesterases and/or phosphodiesterases. These results are consistent with the hypothesis that TRH-stimulated PtdIns(4,5)P2 breakdown causes Ca2+ mobilization leading to prolactin secretion.
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PMID:Thyroliberin stimulates rapid hydrolysis of phosphatidylinositol 4,5-bisphosphate by a phosphodiesterase in rat mammotropic pituitary cells. Evidence for an early Ca2+-independent action. 631 33

We investigated whether prolactin acts at the ovarian level by interfering with the accumulation of gonadotrophin-induced ovarian cyclic AMP. Mouse ovaries were incubated with hCG and varying doses of prolactin. At the end of the incubation, the cyclic AMP which accumulated in the tissue + medium was measured. In ovaries devoid of corpora lutea, a significant inverse correlation (r = -0.93, P less than 0.05) was obtained between the doses of prolactin (0.1-25.6 micrograms ovine prolactin) and hCG-induced accumulation of ovarian cyclic AMP. In the presence of the phosphodiesterase inhibitor IBMX, however, the same doses of prolactin failed to exhibit any restricting influence on the accumulation of cyclic AMP. In luteinized ovaries, the same doses of prolactin in the absence of IBMX did not inhibit the hCG-induced cyclic AMP accumulation.
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PMID:Inhibition by prolactin of gonadotrophin-induced cyclic AMP accumulation in the preovulatory ovary. 632 80

The possible role of calcium as a primary mediator in the control of prolactin secretion from normal pituitary cells was examined. Basal prolactin secretion, and secretion stimulated by thyrotrophin releasing hormone (TRH), raised K+ or the calcium ionophore, A23187, were all dependent on the presence of extracellular Ca2+. The calcium channel antagonists, methoxyverapamil, cobalt and manganese, inhibited basal, TRH- and K+-stimulated prolactin secretion. In addition, prolactin secretion stimulated by a phosphodiesterase inhibitor, isobutylmethylxanthine, which increases cellular cyclic AMP, was inhibited by these Ca2+ antagonists. These observations indicate that Ca2+ may be the primary intracellular mediator in the control of prolactin secretion, with cyclic AMP having a secondary modulatory role on Ca2+ influx, probably on voltage-dependent Ca2+ channels.
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PMID:An investigation of the involvement of calcium in the control of prolactin secretion: studies with low calcium, methoxyverapamil, cobalt and manganese. 672 8

Studies were carried out to determine the possible roles of the polyamines, cyclic nucleotides, icosanoid products, and protein kinase C in the prolactin regulation of amino acid transport in cultured mammary gland explants derived from 12-14 day pregnant mice. Elevated cyclic AMP concentrations impaired the PRL stimulation of AIB transport. DBcAMP as well as the phosphodiesterase inhibitors theophylline and methyl isobutylxanthine, when added to the cultures, attenuated or abolished the PRL responses. 8-Bromo cyclic GMP elicited a modest stimulation of AIB transport. Ongoing polyamine synthesis appears to be necessary for PRL to effect a stimulation of AIB transport since methylglyoxal bis(guanyl hydrazone), an inhibitor of S-adenosyl methionine decarboxylase, abolishes the PRL response; specificity of this effect was established by its reversal with the addition of spermidine to the culture medium. Ongoing icosanoid product synthesis also appears to be required for the PRL stimulation of AIB transport since indomethacin abolishes the PRL response. Finally, the inhibition of the PRL response by the protein kinase C inhibitor H-7 suggests that the activation of kinase C activity may also be involved in the PRL stimulation of AIB transport.
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PMID:Studies on the mechanism by which prolactin stimulates alpha-aminoisobutyric acid uptake into cultured mouse mammary tissues. 769 65

Renin synthesis and secretion from human chorion and decidua have previously been shown to be stimulated by agents which increase cellular cyclic adenosine monophosphate (cAMP). We have now used organ culture of villous placenta, incubated for periods up to 72 h, to investigate the cellular regulation of renin in this tissue. The placental tissues release renin (92-96% in the form of prorenin) and human chorionic gonadotrophin (hCG), but not prolactin. We found that cholera toxin and forskolin markedly stimulate the synthesis and release of renin in a time-dependent manner. This stimulation was potentiated by phosphodiesterase inhibitors and inhibited by an angiotensin II agonist, sar-1-angiotensin II. The inhibitory action of the angiotensin agonist on renin release was blocked by sar-1-leu-8-angiotensin II, a selective angiotensin receptor antagonist. The potential for stimulation of renin expression by cyclic AMP-regulated elements is supported by the dramatic (two-orders of magnitude) increase in renin release observed with cholera and forskolin at 72 h. There are several possible candidates for primary signals for adenylyl cyclase-coupled renin secretion from the placenta, including relaxin and epinephrine. The extremely low concentration of renin in term villous placenta may be related to activation of negative regulatory elements on the renin gene. We propose that angiotensin II is one negative regulator of this system.
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PMID:Prorenin secretion from villous placenta: regulation by cyclic AMP and angiotensin. 799 49

The anterior pituitary gland is a site of nitric oxide (NO) production and action, suggesting a local regulatory function. We recently reported that NO inhibits in vitro prolactin release. The aim of the present study was to establish the mechanism of action of NO on prolactin release and to determine whether NO is involved in the inhibitory effect of GABA on prolactin release. Since NO exerts its action through cGMP by activating guanylate cyclase in different tissues, we examined the effect of sodium nitroprusside (NP), a NO releaser, on intrapituitary cGMP levels. Incubation of anterior pituitary glands with 0.5 mM NP 4-fold increased intrapituitary cGMP content, but decreased intrapituitary cAMP levels. In addition, we studied the effect of NP on prolactin release in the presence of LY 83583, an inhibitor of guanylate cyclase activity and 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of phosphodiesterase activity. 10 microM LY 83583 and 0.5 mM IBMX blocked the inhibitory effect of NP on prolactin release. (10(-3) M) 8Br-cGMP, an analogue of cGMP, mimicked the effect of NP on prolactin release. On the other hand, NO seems to be involved in the inhibitory effect of GABA on prolactin release since hemoglobin, a scavenger of NO, and Nw-nitro-L-arginine methyl ester, an inhibitor of NO synthase (NOS), blocked the pituitary response to GABA. Moreover, GABA (10(-6) M) stimulated NOS activity by almost 50%. GABA increased intrapituitary cGMP levels and decreased cAMP. Dopamine stimulated NOS activity weakly. These observations suggest that NO, acting through the guanylate cyclase-cGMP pathway, inhibits prolactin secretion. In addition, NO may be involved in the inhibitory effect of GABA and dopamine on prolactin release.
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PMID:Role of nitric oxide/cyclic GMP pathway in the inhibitory effect of GABA and dopamine on prolactin release. 895 68

The neuroendocrine system plays a key role in the regulation of the secretion of the thymic peptide, thymulin, but it remains to be determined whether thymulin exerts reciprocal regulatory actions on the functional activity of the hypothalamo-pituitary axis. In the present study, we have used a well established in vitro preparation to examine the influence of thymulin on cyclic nucleotide formation and hormone secretion by the rat anterior pituitary gland. Thymulin-Zn2+ (0.5-50 pM) stimulated the release of immunoreactive corticotrophin (ir-ACTH), producing effects which were maximal at 10 pM (p < 0.01). At the two highest concentrations tested (10 and 50 pM), it also produced small but significant increases in immunoreactive luteinising hormone (ir-LH) release (p < 0.05), but the secretion of immunoreactive growth hormone (ir-GH) was unaffected by the peptide (p > 0.05) while that of immunoreactive prolactin (ir-PRL) was reduced (p < 0.01). The ACTH responses to thymulin were accompanied by increased cyclic nucleotide formation. Thus, thymulin (0.5-50 pM) raised the cyclic 3',5'-adenosine monophosphate (cyclic AMP) content of the pituitary tissue (p < 0.01). At high concentrations (10-50 pM), it also increased cyclic 3',5'-guanosine monophosphate (cyclic GMP; p < 0.01) accumulation, although lower concentrations of the peptide were ineffective in this regard. The increases in ir-ACTH release provoked by thymulin-Zn2+ (0.5-5.0 pM) were potentiated markedly by rolipram (1 microM; p < 0.01), a selective inhibitor of the cyclic-AMP-specific phosphodiesterase enzyme. By contrast, zaprinast (10 microM), a selective inhibitor of cyclic-GMP-specific phosphodiesterase, attenuated the corticotrophic responses to higher concentrations of the peptide (10 and 50 pM; p < 0.05). Neither rolipram (1 microM) nor zaprinast (10 microM) influenced the release of ir-LH, ir-PRL or ir-GH in the presence or absence of thymulin-Zn2+ (0.5-50 pM; p > 0.05). The results suggest that thymulin modulates the secretion of ACTH and possibly LH by the anterior pituitary gland and that its actions are associated with increased cyclic nucleotide formation; in addition, it appears to exert an inhibitory influence on ir-PRL release.
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PMID:Thymulin stimulates corticotrophin release and cyclic nucleotide formation in the rat anterior pituitary gland. 948 96

Islets undergo a number of upregulatory changes to meet the increased demand for insulin during pregnancy, including an increase in glucose-stimulated insulin secretion with a reduction in the stimulation threshold. Treatment with the lactogenic hormone prolactin (PRL) in vitro has been shown to induce changes in islets similar to those observed during pregnancy. We examined cAMP production in islets treated with PRL to determine if changes in cAMP are involved in the upregulation of insulin secretion. Insulin secretion and cAMP concentrations were measured from islets in response to a suprathreshold (6.8 mmol/l) or high (16.8 mmol/l) glucose concentration in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine. Insulin secretion increased by 2.1-, 5.0-, and 5.9-fold at the suprathreshold glucose concentration and by 1.6-, 2.3-, and 2.9-fold at the higher glucose concentration after 1, 3, and 5 days of PRL treatment, respectively. After a similar pattern, cAMP metabolism increased by 1.2-, 1.6-, and 2.1-fold at the suprathreshold glucose concentration and by 1.2-, 1.7-, and 2.2-fold at the high glucose concentration after 1, 3, and 5 days of PRL treatment, respectively. The similar increases in insulin secretion and cAMP concentration suggest that changes in cAMP metabolism are involved in lactogen-induced upregulation of insulin secretion. To gain additional insight into the role of cAMP in the upregulation of islet function after lactogen treatment, we examined the relationship between changes in cAMP concentration and insulin secretion. Under all conditions (differing glucose concentrations and time periods), the increase in insulin release was directly proportional to the increase in cAMP. Thus increased glucose-stimulated insulin secretion from lactogen-treated islets could be accounted for by increased generation of cAMP and did not appear to require any further specific changes in intracellular processes mediated by cAMP. Because the PRL receptor is not directly involved in cAMP metabolism, the lactogen-induced increase in cAMP was most likely due to the increase in glucose metabolism that we have previously demonstrated in PRL-treated islets and in islets during pregnancy.
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PMID:Role of cAMP in upregulation of insulin secretion during the adaptation of islets of Langerhans to pregnancy. 972 31


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