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

---

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

The role of tyrosine kinase(s) in the regulation of cGMP accumulation in rat pinealocytes was investigated using three tyrosine kinase inhibitors. Treatment with genistein, erbstatin or the active analogues of tyrphostin selectively increased basal cGMP accumulation in a dose-dependent manner without a concomitant increase in cAMP. In contrast to the norepinephrine- and vasoactive intestinal peptide-stimulated cGMP responses, the stimulatory effect of genistein was not blocked by the nitric oxide synthase inhibitor NG-monomethyl-L-arginine. Furthermore, in the presence of isobutylmethylxanthine, a phosphodiesterase inhibitor, neither genistein nor erbstatin had an effect on cGMP accumulation. These results indicate that tyrosine kinase inhibitors increase pineal cGMP accumulation through inhibition of the metabolism of cGMP.
...
PMID:Tyrosine kinase inhibitors enhance cGMP production in rat pinealocytes. 753 9

Rat granulosa cell-derived insulin-like growth factor (IGF) binding proteins (BPs) have been found subject to biphasic dose-dependent regulation by FSH under in vitro circumstances. Since cAMP may play an intermediary role in FSH hormonal action, we have undertaken to characterize the A kinase-mediated regulation of the elaboration of IGFBPs by cultured rat granulosa cells. Treatment with increasing concentrations of prostaglandin E2 or choleragen, both established cAMP-generating agonists, produced biphasic dose-dependent regulation of the release of the major 28-29 kilodalton (kDa) IGFBP species while promoting the release of their minor 24 (and 19) kDa counterparts. Similar effects were noted for other cAMP-generating agonists including vasoactive intestinal peptide and forskolin (a potent activator of adenylate cyclase). Moreover, concomitant treatment with a functionally inert low dose (10(-7) M) of forskolin, substantially potentiated the FSH (10 ng/ml)-mediated inhibition of the elaboration of the 28-29 kDa IGFBPs. Application of decreasing dilutions of the invasive adenylate cyclase toxin of bordetella pertussis (but not of an inactive mutant strain) yielded monophasic dose-dependent modulation of the release of the 28-29 kDa IGFBPs while effecting biphasic regulation of the 24 kDa moiety. Concurrent treatment with 1-methyl-3-isobutylxanthine (a potent inhibitor of cAMP phosphodiesterase activity) at the 10(-4) M level resulted in profound (P < 0.05) inhibition of the (low dose) FSH (3 ng/ml)-supported accumulation of the major 28-29 kDa IGFBP species, an effect associated with modest (2.5-fold) induction (P < 0.05) of the minor 24 kDa IGFBP moiety. Lastly, provision of increasing concentrations of nondegradable lipophilic analogs of cAMP (i.e. (Bu)2cAMP and 8-bromoadenosine cAMP resulted in biphasic dose-dependent modulation of the release of the major 28-29 kDa IGFBP doublet while producing an increase in the accumulation of the minor 24 kDa IGFBP species. Taken together, these observations suggest that the ability of low dose FSH to stimulate and of high dose FSH to inhibit the elaboration of the 28-29 kDa IGFBP species may entail activation of the A-kinase transduction pathway. Similar conclusions appear to apply for the ability of FSH to regulate (albeit at a lower response sensitivity level) the biphasic elaboration of the 24 kDa IGFBP moiety. As such, these observations point out the disparate response sensitivities of distinct IGFBP species, thereby suggesting a novel potent mechanism through which FSH may determine the relative distribution pattern of granulosa cell-derived IGFBPs and the consequent overall IGF responsiveness of this cell type.
...
PMID:A kinase-mediated regulation of granulosa cell-derived insulin-like growth factor binding proteins (IGFBPs): disparate response sensitivities of distinct IGFBP species. 768 61

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.
...
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.
...
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

Using an in vitro incubation system, the role of the cyclic AMP-dependent protein kinase A (PKA) pathway in the regulation of the in situ activity of tyrosine hydroxylase (TH) was studied in the hypothalamuses of young and aged ovariectomized rats. Hypothalamic tissue was incubated for 60 min in medium containing 3-hydroxybenzylhydrazine dihydrochloride, a dihydroxyphenylalanine (DOPA) decarboxylase inhibitor, and various agents that modify the activity of the PKA pathway. At the end of the incubation, the tissue was homogenized and analyzed for DOPA and TH mass. The in situ molar activity of TH was expressed as the moles of DOPA accumulating in the tissue per mole of TH per hour. Forskolin, an activator of adenylyl cyclase and the cyclic AMP agonist, (Sp)-cyclic adenosine 3',5'-monophosphothioate, significantly (P < .01) increased the in situ molar activity of TH in the hypothalamic dopaminergic (DAergic) neurons of both young and aged rats. Theophylline, a phosphodiesterase inhibitor, did not affect the TH molar activity in the hypothalamuses of aged animals but did significantly (P < .001) increase its activity in those of young rats. When vasoactive intestinal peptide was evaluated, the TH molar activity was significantly (P < .005) increased in the hypothalamuses of young rats but not in those of aged rats. It was suggested that the deficiency of DA secretion by hypothalamic DAergic neurons of aged rats may be the result of insufficient activation of PKA caused by failure of transduction of an extracellular signal to activate adenylyl cyclase and produce cyclic AMP.
...
PMID:Localization of a defect in hypothalamic dopaminergic neurons of the aged brain that results in impaired PKA-dependent activation of tyrosine hydroxylase. 790 91

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.
...
PMID:Induction of aggregation of Raji human B-lymphoblastic cells by vasoactive intestinal peptide. 810 88

Understanding the mechanisms involved in the biogenesis of N-arachidonoylethanolamine (anandamide) and N-palmitoylethanolamine is important in view of the possible role of these lipids as endogenous cannabinoid substances. Anandamide (which activates cannabinoid CB1 receptors) and N-palmitoylethanolamine (which activates a CB2-like receptor subtype in mast cells) may both derive from cleavage of precursor phospholipid, N-acylphosphatidylethanolamine (NAPE), catalyzed by Ca(2+)-activated D-type phosphodiesterase activity. We report here that the de novo biosynthesis of NAPE is enhanced in a Ca(2+)-dependent manner when rat cortical neurons are stimulated with the Ca(2+)-ionophore ionomycin or with membrane-depolarizing agents such as veratridine and kainate. This reaction is likely to be mediated by a neuronal N-acyltransferase activity, which catalyzes the transfer of an acyl group from phosphatidylcholine to the ethanolamine moiety of phosphatidylethanolamine. In addition, we show that Ca2+-dependent NAPE biosynthesis is potentiated by agents that increase cAMP levels, including forskolin and vasoactive intestinal peptide. Our results thus indicate that NAPE levels in cortical neurons are controlled by Ca2+ ions and cAMP. Such regulatory effect may participate in maintaining a supply of cannabimimetic N-acylethanolamines during synaptic activity, and prime target neurons for release of these bioactive lipids.
...
PMID:Biosynthesis of an endogenous cannabinoid precursor in neurons and its control by calcium and cAMP. 865 87

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.
...
PMID:A novel hypothalamic peptide, pituitary adenylate cyclase-activating peptide, regulates the function of rat granulosa cells in vitro. 883 72

This study was designed to determine the effects of interleukin-1 on basal and prostaglandin E2-stimulated adenosine 3',5'-cyclic monophosphate production by primary and first passage cultures of non-transformed rabbit pigmented and non-pigmented ciliary epithelial cells. Confluent cultures of rabbit pigmented and non-pigmented ciliary epithelial cells were incubated for varying periods of time in serum-free medium with or without interleukin-1 beta, tumor necrosis factor-alpha, bacterial lipopolysaccharide, transforming growth factor-beta 2, cycloheximide, indomethacin and combinations of these agents. Cells were then preincubated for 10 min with serum-free medium plus the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (for basal adenosine 3',5'-cyclic monophosphate production) or serum-free medium containing several concentrations of prostaglandin E2 and 3-isobutyl-1-methylxanthine. In certain experiments isoproterenol, vasoactive intestinal peptide, or forskolin was substituted for prostaglandin E2. Adenosine 3',5'-cyclic monophosphate was then extracted into ice-cold absolute ethanol and measured by radioimmunoassay. Prostaglandin E2 stimulated adenosine 3',5'-cyclic monophosphate production in pigmented and non-pigmented ciliary epithelial cells in a dose-dependent manner. Incubation with interleukin-1 beta (150 U ml-1) increased prostaglandin E2-stimulated, but not basal adenosine 3',5'-cyclic monophosphate production in pigmented ciliary epithelial cells. This interleukin-1 beta-induced enhancement of prostaglandin E2-stimulated adenosine 3',5'-cyclic monophosphate production, called the interleukin-1 effect, was not seen with non-pigmented ciliary epithelial cells. The interleukin-1 effect was dependent upon interleukin-1 beta concentration, time and de novo protein synthesis. The interleukin 1 effect could not be reproduced by replacing interleukin-1 beta with tumor necrosis factor-alpha or bacterial lipopolysaccharide and was specific for prostaglandin E2, since interleukin-1 beta did not enhance isoproterenol-, vasoactive intestinal peptide-, or forskolin-induced adenosine 3',5'-cyclic monophosphate production. Chronic exposure to prostaglandin E2 (during the 3 hr incubation period), with or without interleukin-1 beta in the incubation medium, reduced subsequent prostaglandin E2-stimulated adenosine 3',5'-cyclic monophosphate production. Inhibition of de novo prostaglandin synthesis with indomethacin increased the interleukin-1 effect. The interleukin-1 effect was inhibited by the immunosuppressive cytokine, transforming growth factor-beta 2, in a dose-dependent manner. This is the first report of prostaglandin E2-induced stimulation of adenosine 3',5'-cyclic monophosphate production by pigmented ciliary epithelial cells and of the unique ability of interleukin-1 to increase this effect. The results are consistent with interleukin-1-induced upregulation of prostaglandin E receptors. Since transforming growth factor-beta 2 inhibited this interleukin-1 effect, this immunosuppressive cytokine may exert negative feedback and thus regulate the physiological consequences of the interleukin-1 effect.
...
PMID:Interleukin-1 beta increases prostaglandin E2-stimulated adenosine 3',5'-cyclic monophosphate production in rabbit pigmented ciliary epithelium. 898 69

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.
...
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


<< Previous 1 2 3 4 5 6 7 8 9 Next >>

---