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)

Chronic ethanol consumption significantly increases gastric adenylate cyclase (AC) activity (p less than 0.05) without influencing low Km 3',5'-cyclic adenosine monophosphate (cAMP) phosphodiesterase (PD) activity in the rat. On the other hand, in the duodenum and upper part of the jejunum, chronic ethanol feeding leads to a significant decrease of adenylate cyclase activity (p less than 0.02) and, again, does not affect low Km cAMP phosphodiesterase activity. In addition, the effect of various hormonal secretagoques on small intestinal adenylate cyclase activity was investigated. Prostaglandin I2 and D2, as well as glucagon, do not stimulate AC at all. However, small intestinal adenylate cyclase exhibits a lower sensitivity to prostaglandin E2 and vasoactive intestinal peptide (VIP), and a lower efficacy to VIP after chronic ethanol consumption when compared to controls. The decrease of both basal and stimulated AC activity following ethanol ingestion in the upper small intestine may be due to membrane alterations and tissue damage caused by ethanol. The ethanol-induced increase in gastric AC may be of relevance with respect to an increased acid secretion observed after alcohol administration.
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PMID:Effect of chronic ethanol ingestion on the cyclic AMP system of the upper gastrointestinal tract in the rat. 631 89

In this study, vasoactive intestinal peptide (VIP) is shown to inhibit substrate adherence capacity of rat peritoneal macrophages. The inhibitory response occurred in the 0.1-1,000 nM range of VIP concentrations and it was a time-dependent process. At 15 min, half maximal inhibition (IC50) was obtained at 0.37 +/- 0.26 nM and maximal inhibition (53.8%) at 10(-6) M VIP. The inhibitory effect of VIP was correlated with the stimulation by this peptide of cyclic AMP (cAMP) production in rat peritoneal macrophages. Moreover, agents that inhibited VIP-stimulated cAMP production, such as the VIP-antagonist [4-Cl-D-Phe6, Leu17]-VIP and somatostatin, also decreased the inhibitory effect of VIP on substrate adherence capacity of macrophages. On the contrary, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) and the lipid-soluble derivative of cAMP N6,2'-O-dibutyryl cAMP (Bu-cAMP) inhibited the adherence of macrophages to substrate and potentiated the inhibitory action of VIP. These results demonstrate that VIP inhibits substrate adherence capacity of rat peritoneal macrophages by a mechanism that involves cAMP, and show, for the first time, an action of VIP on the function of peritoneal macrophages.
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PMID:Vasoactive intestinal peptide (VIP) inhibits substrate adherence capacity of rat peritoneal macrophages by a mechanism that involves cAMP. 752 55

Although secretin and vasoactive intestinal peptide (VIP) stimulate production of the second-messenger substance cyclic AMP and exert a positive inotropic action on rat ventricle in vitro, a direct action of these peptides on cardiomyocytes has not been established. In contrast to hearts of other mammalian species, which possess VIP-preferring receptors, rat heart is unique in that the existence of a "relatively nonselective receptor" at which both secretin and VIP may bind has been proposed. We wished to define the receptor(s) for secretin and VIP present on rat ventricular cardiomyocytes using a homogeneous suspension of viable cells. With adenosine deaminase 5 U/ml and the phosphodiesterase (PDE) inhibitor isobutyl methylxanthine (IBMX) 1 mM, both secretin and VIP increased intracellular levels of cyclic AMP maximally and concentration dependently after 5 min: EC50 values were 8 and 58 nM, respectively. At maximally effective concentrations, secretin 1 microM increased intracellular levels of cyclic AMP fourfold above basal levels, whereas a 1.6-fold increase was induced by VIP 10 microM. Maximum changes in cell length (dL) of isolated cardiomyocytes during electrically stimulated (0.5 Hz) contractions were determined in the presence of adenosine deaminase 2.5 U/ml. Under these conditions, both secretin and VIP produced a concentration-dependent positive contractile response that became maximal 5 min after addition of the peptide. Secretin 50 nM increased the amplitude of cellular contractions maximally to a value 37% greater than that obtained without peptide. VIP 20 nM increased the amplitude of cellular contractions maximally to a value 19% greater than that obtained without peptide. The EC50 values were 470 and 700 pM for VIP and secretin, respectively. The selective antagonist at VIP-preferring receptors, 4-Cl DPhe-6 Leu-17 VIP 10 microM did not antagonise the actions of VIP. In the presence of the selective antagonist at receptors for secretin, secretin 7-27 > or = 10 microM, the concentration dependence of the effect of secretin on accumulation of cellular cyclic AMP and contractile amplitude displayed a rightward parallel shift: the pA2 value for secretin 7-27 was 4.96. Secretin 7-27 also induced a rightward parallel shift of the concentration dependence of the actions of VIP. VIP 10 microM was additive with low concentrations of secretin (< 10 nM) in stimulating production of cyclic AMP but antagonised this response at higher concentrations of secretin (> 10 nM). Similarly, VIP 2 and 20 nM enhanced the contractile response to low concentrations of secretin (< 1 nM), but antagonised the response at higher concentrations of secretin (> 1 nM).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Secretin and vasoactive intestinal peptide are potent stimulants of cellular contraction and accumulation of cyclic AMP in rat ventricular cardiomyocytes. 752 89

The synthesis of the neuropeptide precursor proenkephalin was measured in bovine adrenal chromaffin cells following radiolabeling with [35S]methionine. Treatment of chromaffin cells with pertussis toxin (100 ng/ml) approximately doubled proenkephalin synthesis without altering total protein synthesis. Pertussis toxin pretreatment also increased proenkephalin synthesis in chromaffin cells exposed to vasoactive intestinal peptide (VIP) and 3-isobutyl-1-methylxanthine (IBMX). Combinations of IBMX plus nicotine, VIP, or histamine also synergistically enhanced proenkephalin synthesis, with no further elevation when the cells were also pretreated with pertussis toxin. The action of forskolin, a direct activator of adenylate cyclase, on proenkephalin synthesis was similarly potentiated by pertussis toxin or IBMX, presumably reflecting the abilities of both the toxin and this phosphodiesterase inhibitor to enhance the cyclic AMP response to forskolin. In contrast, increased synthesis of proenkephalin in response to phorbol esters was not affected by pertussis toxin treatment. These results suggest that pertussis toxin potentiates proenkephalin synthesis primarily through inactivation of guanine nucleotide-binding proteins that inhibit adenylate cyclase, although other signaling pathways may also be involved.
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PMID:Pertussis toxin enhances proenkephalin synthesis in bovine chromaffin cells. 769 72

The regulation of intracellular free Ca2+ concentration was examined in single dissociated chick pineal cells using the fura-2 technique. Approximately 10% of cells examined exhibited spontaneous Ca2+ oscillations while the rest were quiescent. Application of salines containing 80 mM KCl evoked large increases in intracellular free Ca2+ that were dependent upon external Ca2+ ions. These responses were inhibited by 10 microM nifedipine indicating involvement of L-type Ca2+ channels. Application of the tumor promoter thapsigargin (2 microM) evoked increases in intracellular free Ca2+. These responses could be observed in the absence of external Ca2+ indicating mobilization of internal stores. In the absence of external Ca2+, the responses to thapsigargin gradually decayed due to depletion of internal Ca2+ pools. A subsequent exposure to saline containing 5.8 mM CaCl2 caused a rapid increase in intracellular Ca2+ that was consistently larger than the peak response to thapsigargin. Application of 100 nM vasoactive intestinal peptide (VIP), a neurohormone that stimulates melatonin secretion from pineal cells, induced a sustained increase in intracellular free Ca2+ in a subpopulation of cells. In a small number of cells, VIP evoked Ca2+ oscillations. Approximately half of the cells examined showed no response to VIP. Application of 200 microM norepinephrine, which inhibits melatonin secretion from the chick pineal, had no effect on intracellular free Ca2+ in any quiescent or spontaneously oscillating cells. Application of 5 mM 8-Br-cAMP evoked sustained increases in intracellular Ca2+. Similar effects were obtained with the phosphodiesterase inhibitors papaverine (50 microM) or isobutylmethylxanthine (100 microM). Application of 200 nM forskolin, an activator of adenylate cyclase, evoked increases in intracellular free Ca2+ that could be detected in the presence of 10 microM nifedipine. The responses to forskolin gradually decayed in Ca(2+)-free external salines due to depletion of intracellular Ca2+ stores. Subsequent exposure to external Ca2+ caused a rapidly developing increase in intracellular Ca2+ that was larger than the peak response to forskolin. These results indicate that the regulation of intracellular free Ca2+ in chick pineal cells is complex. These cells exhibit Ca2+ oscillations and can mobilize both external and internal Ca2+ pools. Agents that increase intracellular cAMP cause mobilization of internal Ca2+ stores, possibly secondary to effects on other second messenger systems. Chick pineal cells, like many other cell types, possess mechanisms to allow for refilling of depleted internal Ca2+ stores. These results suggest new mechanisms for the regulation of melatonin synthesis and secretion and possible sites of action for the intrinsic circadian oscillator.
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PMID:Intracellular free Ca2+ in dissociated cells of the chick pineal gland: regulation by membrane depolarization, second messengers and neuromodulators, and evidence for release of intracellular Ca2+ stores. 780 49

Subsets of neurons in the thymic cortex, Peyer's patches and lymphoid tissues of the respiratory system deliver vasoactive intestinal peptide (VIP) at nanomolar concentrations. The possible effects of VIP on B-cell adhesiveness in these tissues were examined in studies of the homotypic aggregation (HA) of human B-lymphoblastoid cells of the Raji line, which express a mean of 27,950 VIP receptors/cell with a mean Kd of 0.8 nM. Mean HA, assessed microscopically, attained a maximum of 54% after 8 hr with 0.1 microgram/ml of phorbol 12-myristate 13-acetate (PMA) (P < 0.01) and 31% after 24 hr with 10(-8) M VIP (P < 0.05), as contrasted with 13% and 20% at the respective times in medium alone, and both stimuli also increased the mean size of aggregates. The presence of the phosphodiesterase inhibitor Ro 20-1724 permitted 10(-9) M VIP, which had no effect alone, to raise the mean cyclic AMP content of Raji cells by more than 10-fold and concurrently to elevate mean HA from 55% in medium alone at 48 hr to 70% and from 55% at 72 hr to 68% (P < 0.05 for both). Monoclonal antibodies to lymphocyte function-associated (LFA-1) adhesive protein and to intercellular adherence molecule-1 (ICAM-1) suppressed significantly the HA of Raji cells induced by VIP and PMA. The effects of VIP on compartmental immunity in the lungs and intestines thus may be mediated in part by increases in lymphocyte adhesiveness, which could contribute to the regional accumulation of specifically immunocompetent cells.
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PMID:Induction of aggregation of Raji human B-lymphoblastic cells by vasoactive intestinal peptide. 810 88

Pituitary adenylate cyclase-activating peptide (PACAP) is a novel peptide that was isolated from ovine hypothalamic tissue on the basis of its ability to stimulate cAMP accumulation in cultured rat pituitary cells. Recently we demonstrated that PACAP can stimulate cAMP accumulation and secretory function in cultured rat Sertoli cells. Since ovarian granulosa cells share many properties with Sertoli cells, we have examined the effect of PACAP (consisting of 38 or 27 amino acid residues) on cultured granulosa cell function. Granulosa cells were obtained from the ovaries of 25-day-old rats implanted with a silastic capsule containing diethylstilbestrol 5 days prior to culture. PACAP 38 (0.1 microM-0.01 pM), both alone and in the presence of the phosphodiesterase inhibitor, methylisobutylxanthine, stimulated cAMP accumulation 4-8-fold with an ED50 of approximately 100 pM. Maximal PACAP 38 or PACAP 27 stimulation of granulosa cell cAMP was significantly greater than that produced by a maximally effective concentration of FSH. Because PACAP 38 and 27 have 68% sequence homology with vasoactive intestinal peptide (VIP), and since VIP stimulates granulosa cell cAMP accumulation and estradiol and progesterone secretion, we examined the possibility that PACAP could be acting via the VIP receptor. VIP stimulated cAMP only at concentrations of 10 nM or greater, whereas the PACAP stimulation was evident at 10 pM. Moreover, only one of three potent VIP antagonists inhibited VIP stimulation of cAMP accumulation, and only at 1 microM or greater. This VIP antagonist did not inhibit PACAP 38 action at 2000-fold excess concentration. Interestingly PACAP 38 was more effective than PACAP 27 with regard to steroid secretion and the ability to induce LH responsiveness. PACAP and VIP stimulation of granulosa cell cAMP accumulation or estradiol or progesterone secretion was not additive. Thus, these data support the hypothesis that granulosa cells have specific PACAP 38 receptors and that VIP acts via these receptors. In addition, PACAPs 38 and 27 are more potent stimulators of cAMP accumulation in luteinized granulosa cells than LH. These results both pre- and postovulation, along with previous data indicating that the PACAPs are found in the ovaries, suggest a role for PACAP in the regulation of ovarian function.
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PMID:A novel hypothalamic peptide, pituitary adenylate cyclase-activating peptide, regulates the function of rat granulosa cells in vitro. 883 72

Granulosa cells are known to be the site of action of various hormones and agents that regulate ovarian function. This study was conducted to evaluate the effects of gonadotrophins, vasoactive intestinal peptide (VIP), prostaglandin (PG) F2 alpha and angiotensin II on the cyclic AMP (c-AMP) signalling transduction pathway in human granulosa-lutein cells. Exposure to agents that elevate c-AMP or mimic c-AMP action caused the cells to become rounded in a process that was rapid and reversible. We were able to demonstrate this cell rounding process in the presence of gonadotrophins and VIP, but not in the presence of PGF 2 alpha or angiotensin II. In addition, incubation of the cells with various selective phosphodiesterase (PDE) inhibitors revealed that the PDE type IV isoform, but not type III, catalyses c-AMP degradation in human granulosa-lutein cells. Alteration in c-AMP-dependent cytomorphology appears to be a convenient method to analyse the regulation of c-AMP-mediated events in the human granulosa-lutein cells.
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PMID:Cell shape change reveals the cyclic AMP-mediated action of follicle stimulating hormone, human chorionic gonadotrophin and vasoactive intestinal peptide in primary cultured human granulosa-lutein cells. 923 88

The heavy metal cadmium causes nephrotoxicity and alters the transport function of epithelial cells. In the shark rectal gland, chloride secretion is regulated by secretagogues and inhibitors acting through receptors coupled to G proteins and the cyclic AMP-protein kinase A pathway. We examined the effects of cadmium on the response to the inhibitory peptide somatostatin (SRIF), and to the stimulatory secretagogues forskolin and vasoactive intestinal peptide (VIP). In control experiments, SRIF (100 nM) entirely inhibited the chloride secretory response to 10 microM forskolin (maximum chloride secretion with forskolin 1984 +/- 176 microEq/h/g; with forskolin + SRIF 466 +/- 93 microEq/h/g, P < 0.001). Cadmium (25 microM) entirely reversed the inhibitory response to SRIF (chloride secretion 2143 +/- 222 microEq/h/g) and caused an overshoot (2917 +/- 293 microEq/h/g) that exceeded the response to forskolin (P < 0.01). Cadmium also enhanced forskolin-stimulated chloride secretion (2628 +/- 418 vs. 1673 +/- 340 microEq/h/g, P < 0.02) and reversed the declining phase of the forskolin response. Cadmium had a concentration-dependent, biphasic effect on the response to VIP. Cd (10-100 microM) increased both chloride secretion and tissue cyclic AMP content, whereas higher concentrations (1 mM) inhibited chloride secretion and cyclic AMP accumulation. Our findings provide evidence that Cd disrupts the signal transduction pathways of both inhibitory receptors and secretagogues regulating cAMP mediated transport in an intact epithelia. The results are consistent with direct effects of cadmium on adenylate cyclase and/or phosphodiesterase activity in this marine epithelial model.
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PMID:Cadmium disrupts the signal transduction pathway of both inhibitory and stimulatory receptors regulating chloride secretion in the shark rectal gland. 939 74

At inflammatory sites, leukocytes may confront multiple, competing chemoattractive signals. We compared the chemotactic potencies of several sensory neuropeptides with regard to signal transduction pathways in eosinophils. Eosinophils were enriched using magnetic cell sorting and migration was assayed in a Boyden microchemotaxis chamber. We found stimulatory effects of substance P, calcitonin gene-related peptide (CGRP), secretoneurin, vasoactive intestinal peptide (VIP), and secretin on eosinophil migration. Actions of VIP are predominantly mediated via VIP receptor type I. Migration toward secretoneurin, VIP, and secretin was blocked by a phosphodiesterase inhibitor, which, in contrast failed to affect substance P- and CGRP-induced eosinophil chemotaxis. Wortmannin blunted the migratory responses induced by all neuropeptides tested and substance P-induced effects on eosinophils were tyrphostin-23-sensitive. We conclude that substance P, CGRP, secretoneurin, and VIP/secretin stimulate eosinophil migration involving wortmannin-sensitive enzymes. Moreover, secretoneurin and VIP/secretin require additional activation of phosphodiesterases to stimulate eosinophil migration.
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PMID:Signaling in neuropeptide-induced migration of human eosinophils. 985 Jan 67


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