Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An important factor in regulating secretion from endocrine cells is the cytoplasmic concentration of cyclic-AMP. Many regulatory substances are known to either stimulate or inhibit the production of this second messenger through activation of their receptors. In the present study, we have monitored changes in cyclic-AMP efflux from melanotrope cells of Xenopus laevis in response to established neurochemical regulators of alpha-MSH secretion. In vitro superfusion of neurointermediate lobes allows for a dynamic recording of cyclic-AMP production in relation to hormone secretion. Unlike alpha-MSH secretion, the efflux of cyclic-AMP was not dependent on the concentration of extracellular calcium, indicating that hormone release and cyclic-AMP efflux are mediated by different mechanisms. The phosphodiesterase inhibitor IBMX and the adenylate cyclase activator forskolin stimulated cyclic-AMP efflux, but had no stimulatory effect on alpha-MSH release. This indicates that an increase in cyclic-AMP production in melanotrope cells is not necessarily accompanied by an increase in the rate of alpha-MSH release. Corticotropin-releasing factor stimulated cyclic-AMP efflux with dynamics similar to that induced by the amphibian peptide sauvagine. Dopamine and the GABAB receptor agonist baclofen both inhibited cyclic-AMP efflux and alpha-MSH release, with similar dynamics of inhibition and similar dose-response relationships. It is proposed that an inhibition of cyclic-AMP efflux is coupled to an inhibition of alpha-MSH secretion.
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PMID:Dynamics of cyclic-AMP efflux in relation to alpha-MSH secretion from melanotrope cells of Xenopus laevis. 127 39

The potentiation of corticotropin-releasing factor (CRF)-stimulated cAMP production by vasopressin (VP) in the pituitary cell was investigated by studies on the interaction of CRF, VP, and the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA) on cAMP, adenylate cyclase and phosphodiesterase. Addition of VP or PMA (0.01-100 nM) alone did not alter cellular cAMP content, but markedly increased the effect of 10 nM CRF with ED50 of about 1 nM. Treatment of the cells with 200 ng/ml pertussis toxin for 4 h increased CRF-stimulated cAMP accumulation by 3.2-fold, an effect that was not additive to those of VP and PMA. Incubation of pituitary cells with 2 mM 1-methyl-3-isobutylxanthine increased CRF-stimulated cAMP accumulation and decreased the relative effect of VP and PMA, suggesting that the actions of VP and PMA are partially due to inhibition of phosphodiesterase. This was confirmed by the demonstration of a 30% inhibition of the low-affinity phosphodiesterase activity in cytosol and membranes prepared from cells preincubated with VP or PMA. In intact cells, following [3H]adenine prelabeling of endogenous ATP pools, measurement of adenylate cyclase in the presence of 1-methyl-3-isobutylxanthine showed no effect of VP and PMA alone, but did show a 2-fold potentiation of the effect of CRF. Measurement of adenylate cyclase in pituitary homogenates by conversion of [alpha-32P]ATP to [32P]cAMP showed a paradoxical GTP-dependent inhibition by VP of basal and CRF-stimulated adenylate cyclase activity, suggesting that the VP receptor is coupled to an inhibitory guanyl nucleotide-binding protein. Pertussis toxin pretreatment of the cells prevented the VP inhibition of adenylate cyclase activity observed in pituitary cell homogenates. These findings indicate that besides inhibition of phosphodiesterase, VP has a dual interaction with the pituitary adenylate cyclase system; a direct inhibitory effect, manifested only in broken cells, that is mediated by a receptor-coupled guanyl nucleotide-binding protein, and a physiologically predominant indirect stimulatory effect in the intact cell, mediated by protein kinase C phosphorylation of one of the components of the CRF-activated adenylate cyclase system.
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PMID:Phorbol 12-myristate 13-acetate and vasopressin potentiate the effect of corticotropin-releasing factor on cyclic AMP production in rat anterior pituitary cells. Mechanisms of action. 243 73

Oocytes of the African frog Xenopus laevis are shown by electrophysiological methods to possess receptors for corticotropin-releasing factor (CRF), arginine-vasopressin (AVP) and cholecystokinin (CCK). Oocytes surrounded by their follicular cell envelope responded to CRF or AVP with an outward hyperpolarizing current. This current was mediated by an increased conductance of K+ ions. Pretreatment with the adenylate cyclase activator forskolin or with the cAMP phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) potentiated the responses to these peptides indicating that the cAMP second messenger system may mediate the responses. Oocytes stripped of the follicular envelope, which cannot generate cAMP-dependent K+ currents, did not respond to either CRF or AVP. Oocytes exposed to CCK responded with an inward depolarizing current. This current was carried by an increased conductance to Cl-ions. Removal of the follicular cell layer did not affect the response to CCK. The shape, time course, and reversal potential of the Cl-current suggest that CCK acts through the phosphatidylinositol pathway.
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PMID:Activation of ionic currents in Xenopus oocytes by corticotropin-releasing peptides. 285 83

The AtT-20/D16-16 mouse pituitary tumor cell secretes corticotropin (ACTH) in response to corticotropin-releasing factor (CRF), (-)-isoproterenol, and vasoactive intestinal peptide (VIP). These responses are associated with a rapid increase in cyclic AMP formation. Somatostatin (SRIF) markedly decreases the stimulatory effect of CRF, (-)-isoproterenol, and VIP on both cyclic AMP formation and immunoreactive ACTH secretion. Forskolin and cholera toxin, adenylate cyclase activators, also stimulate cyclic AMP formation and ACTH secretion in AtT-20 cells and these responses are all inhibited by SRIF. The ACTH secretory responses to melittin and to the calcium ionophore A23187, neither of which increases cyclic AMP in AtT-20 cells, were not inhibited by SRIF. SRIF did not affect the binding of a tritiated beta-adrenergic receptor antagonist to AtT-20 membranes nor did it decrease basal cyclic AMP formation even in the presence of excess phosphodiesterase inhibitor, indicating that the reduction of cyclic AMP levels by SRIF did not involve either an interference with beta-adrenergic agonist binding to receptors or stimulation of cyclic AMP degradation. These results indicate that the inhibition of CRF-, (-)-isoproterenol-, and VIP-stimulated ACTH secretion by SRIF may be regulated by its inhibitory action on adenylate cyclase.
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PMID:Somatostatin inhibits multireceptor stimulation of cyclic AMP formation and corticotropin secretion in mouse pituitary tumor cells. 612 32

Addition of somatostatin-14 (SRIF) inhibits corticotropin releasing factor (CRF) and forskolin-stimulated cyclic AMP formation and ACTH release from tumor cells of the mouse anterior pituitary (AtT-20/D16-16). After long-term pretreatment of these cells with SRIF, the ability of SRIF to inhibit CRF and forskolin-stimulated cyclic AMP accumulation or ACTH secretion is markedly reduced. SRIF pretreatment also increases the formation of cyclic AMP in response to forskolin. This increase is delayed in onset, slow to recover, and blocked by the protein synthesis inhibitor, cycloheximide. SRIF pretreatment did not affect basal cyclic AMP and cyclic GMP levels or phosphodiesterase activity. It is proposed that prolonged treatment of AtT-20 cells with SRIF desensitizes SRIF receptors and induces a compensatory sensitization of adenylate cyclase through a process requiring protein synthesis.
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PMID:Prolonged somatostatin pretreatment desensitizes somatostatin's inhibition of receptor-mediated release of adrenocorticotropin hormone and sensitizes adenylate cyclase. 613

Addition of somatostatin (SRIF) inhibits corticotropin-releasing factor- and forskolin-stimulated cyclic AMP accumulation and adrenocorticotropin hormone secretion from mouse anterior pituitary tumor cells (AtT-20/D16-16). However, prior exposure of these cells to SRIF reduced the potency of SRIF to inhibit both corticotropin-releasing factor- and forskolin-stimulated cyclic AMP accumulation and adrenocorticotropin hormone release. This SRIF desensitization is time- and concentration-dependent and reversible. Cross-desensitization to SRIF analogs also occurred whereas SRIF pretreatment did not affect the inhibition by SRIF of 8-bromo-cyclic AMP-stimulated adrenocorticotropin hormone release or did it affect basal cyclic AMP levels, protein content or phosphodiesterase activity. These data indicate that SRIF can regulate the sensitivity of its own receptor and that SRIF desensitization may involve either a down-regulation of SRIF receptors or an uncoupling of these inhibitory receptors from adenylate cyclase.
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PMID:Somatostatin desensitization: loss of the ability of somatostatin to inhibit cyclic AMP accumulation and adrenocorticotropin hormone release. 614 43

The present study examined the involvement of prostaglandins (PGs) in the mechanisms of ACTH and beta-endorphin release from rat anterior pituitary quarters incubated in vitro. Various cyclooxygenase inhibitors (indomethacin, diclofenac, flurbiprofen) had no effect on basal release of ACTH-like or beta-endorphin-like immunoreactivity (beta-EI), but enhanced ACTH-immunoreactivity/beta-EI release upon stimulation by arginine-vasopressin (AVP) or synthetic ovine corticotropin-releasing factor [CRF-(1-41)]. The lowest effective concentration of indomethacin was just sufficient to prevent PG synthesis. Indomethacin was similarly active after blockade of the phosphodiesterase by 3-isobutyl-1-methylxanthine. When added to the incubation media in concentrations up to 1 microM, PGE2, D2, F2 alpha, or prostacyclin (PGI2) did not alter basal beta-EI release; however, with stimulation by AVP or CRF-(1-41), PGE2 but not PGD2, F2 alpha, or I2 inhibited beta-EI release by about 60%. The concentrations of PGE2 in the incubation media, as measured by RIA, were somewhat higher than those of any other cyclooxygenase product (PGD2, F2 alpha, 6-keto-PGF1 alpha, thromboxane B2). Upon stimulation by AVP or CRF-(1-41), the concentrations of PGE2 increased, whereas those of PGD2 or F2 alpha remained unchanged. The release of beta-EI stimulated by high potassium concentration was not enhanced by indomethacin, although this release was sensitive to inhibition by PGE2. We conclude that PGE2 is formed locally subsequent to binding of the neurohormones and may act as a negative feedback-modulator of vasopressin's and CRF-(1-41)'s activity in the anterior pituitary gland.
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PMID:Adrenocorticotropin and beta-endorphin release from rat adenohypophysis in vitro: inhibition by prostaglandin E2 formed locally in response to vasopressin and corticotropin-releasing factor. 620 54

The role of cyclic AMP in the stimulation of corticotropin (ACTH) release by corticotropin-releasing factor (CRF), angiotensin II (AII), vasopressin (VP), and norepinephrine (NE) was examined in cultured rat anterior pituitary cells. Synthetic CRF rapidly stimulated cyclic AMP production, from 4- to 6-fold in 3 min to a maximum of 10- to 15-fold at 30 min. Stimulation of ACTH release by increasing concentrations of CRF was accompanied by a parallel increase in cyclic AMP formation, with ED50 values of 0.5 and 1.3 nM CRF for ACTH and cyclic AMP, respectively. A good correlation between cyclic AMP formation and ACTH release was also found when pituitary cells were incubated with the synthetic CRF(15-41) fragment, which displayed full agonist activity on both cyclic AMP and ACTH release with about 0.1% of the potency of the intact peptide. In contrast, the CRF(21-41) and CRF(36-41) fragments were completely inactive. The other regulators were less effective stimuli of ACTH release and caused either no change in cyclic AMP (AII and VP) or a 50% decrease in cyclic AMP (NE). Addition of the phosphodiesterase inhibitor, methylisobutylxanthine, increased the sensitivity of the ACTH response to CRF but did not change the responses to AII, VP, and NE. In pituitary membranes, adenylate cyclase activity was stimulated by CRF in a dose-dependent manner with ED50 of 0.28 nM, indicating that the CRF-induced elevation of cyclic AMP production in intact pituitary cells is due to increased cyclic AMP biosynthesis. The intermediate role of cyclic AMP in the stimulation of ACTH release by CRF was further indicated by the dose-related increase in cyclic AMP-dependent protein kinase activity in pituitary cells stimulated by CRF with ED50 of 1.1 nM. These data demonstrate that the action of CRF on ACTH release is mediated by the adenylate cyclase-protein kinase pathway and that the sequence requirement for bioactivity includes the COOH-terminal 27 amino acid residues of the molecule. The other recognized regulators of ACTH release are less effective stimuli than CRF and do not exert their actions on the corticotroph through cyclic AMP-dependent mechanisms.
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PMID:Mechanisms of action of corticotropin-releasing factor and other regulators of corticotropin release in rat pituitary cells. 630 67

The corticotropin releasing factor (CRF) receptor is known to be coupled to Gs and transduces its signal through stimulation of cyclic AMP (cAMP) production. Here we describe the characterization of several stable CRF receptor-expressing LVIP2.0Zc cell lines that also contain an exogenous cAMP-responsive beta-galactosidase reporter gene construct. The CRF receptor activity was assayed by measuring the induction of beta-galactosidase in response to CRF. Rat/human and bovine CRF stimulated beta-galactosidase activity in a dose-dependent manner with EC50 values of approximately 0.1 nM; the biologically weak deamidated analog of bovine CRF was approximately 500-fold less potent. The CRF receptor antagonist, [d-Phe12,Nle21,38,Ala32]r/hCRF(12-41) produced a dose-dependent inhibition of CRF-stimulated beta-galactosidase activity, further demonstrating the pharmacological specificity of the interaction. The magnitude of the maximal response to CRF varied among individual cell lines. This variation was independent of the level of CRF receptor expression, but reflected differences in the intrinsic activity of adenylate cyclase. In contrast to most cAMP assay systems, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine decreased the CRF-induced beta-galactosidase activity when used in the context of the assay regimen described here. Since the assay can be easily performed in a high-throughput 96-well plate format, these cell lines provide an efficient way for the identification of CRF receptor agonists and antagonists.
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PMID:Colorimetric assay for rapid screening of corticotropin releasing factor receptor ligands. 753 19

Cyclic nucleotide phosphodiesterases (PDEs) appear to play a major role in the modulation of cellular accumulations of cAMP/cGMP and hence the magnitude of the cell response to a hormone signal. These enzymes are present in cells as multiple isoforms and lie under control of various protein kinases. Because PACAP, unlike corticotropin-releasing factor (CRF), may stimulate a dual signalling pathway in pituitary cells (activating both adenylyl cyclase and phospholipase C), we used AtT-20 corticotrophs and primary cultures of rat pituitary cells to study the effect and possible differential influence of these peptides on cAMP formation. Time-course analysis indicated that, both in the absence and the presence of Rolipram (a selective type IV PDE inhibitor), PACAP stimulated a rapid and short-lived accumulation of cAMP in tumor corticotrophs, while in the presence of the non-selective inhibitor IBMX, the peptide produced a sustained high plateau level of second messenger (10 times the level generated with Rolipram at 20 min). On the contrary, when exposed to CRF, cAMP production augmented in parallel, irrespective of whether Rolipram or IBMX were present. The differential effects of the PDE inhibitors were seen with PACAP concentrations ranging from 0.1 to 100 nM, and could also be demonstrated in primary cultures of pituitary cells. Co-incubation of AtT-20 cells with Rolipram along with inhibitors of type I (but not of type III) PDEs, enhanced cAMP formation elicited by PACAP to a level significantly higher than that induced by CRF.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Multifactorial regulation of pituitary adenylate cyclase-activating polypeptide (PACAP)-induced production of cyclic AMP in ATT-20 corticotrophs: major involvement of Rolipram-sensitive and insensitive phosphodiesterases. 758 82


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