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)

Changes in the content of cyclic nucleotides (cAMP and cGMP) and related enzyme activities were observed in the rat thyroid, pituitary and plasma during the prolonged increase of endogenous TSH produced by treatment with methylthiouracil (MTU). Experiments were performed after 4 weeks treatment with MTU. The wet weight and cAMP content per wet weight of the thyroid increased 3 and 1.4 times respectively, but cGMP showed a slight decrease. Pituitary weight increased 1.3 times, but cAMP and cGMP content did not change. The cAMP level in plasma also increased about 1.3 times, but cGMP did not increase. The cAMP-phosphodiesterase activity in the thyroid, pituitary and plasma was increased 1.9, 1.4 and 1.3 times respectively after MTU treatment, while cGMP-phosphodiesterase showed no significant change. ATPase activity in the thyroid and pituitary was also increased more than 1.5 times after MTU treatment, while 5'-nucleotidase activitity decreased remarkably. These data indicate that the metabolism of the cyclic nucleotide system in the thyroid is stimulated by TSH.
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PMID:Changes in the cyclic nucleotides of rat thyroid, pituitary and plasma caused by methylthiouracil treatment. 21 61

A number of regulatory peptides were investigated for their ability to elevate plasma cAMP. Pituitary adenylate cyclase activating peptide (PACAP)-27, PACAP-38, helodermin, helospectin I and II, vasoactive intestinal peptide (VIP), glucagon, parathyroid hormone (PTH), calcitonin and calcitonin gene-related peptide were among the peptides that were highly effective in raising plasma cAMP when given intravenously in equimolar doses to conscious mice. PACAP-27 and -38 were more effective than any of the other peptides. PACAP 16-38, secretin, gastrin-17, galanin, somatostatin, cholecystokinin-8s, pancreatic polypeptide, substance P, peptide YY and neuropeptide Y were inactive and also did not interfere with the PACAP-27-evoked rise in plasma cAMP levels. Repeated injections of PACAP-27 every 30 min caused a progressive reduction in the plasma cAMP response (measured 5 min after each injection). Forskolin, an activator of adenylate cyclase, dose-dependently raised the plasma concentration of cAMP and displayed a synergistic effect when given in a low dose concurrently with PTH or PACAP-38. The phosphodiesterase inhibitor rolipram dose-dependently raised the plasma concentration of cAMP. Combined treatment with PACAP-27 and a threshold dose of rolipram resulted in an exaggerated plasma cAMP response. Kidney hilus ligation suppressed the responses to PACAP-38, PTH, helodermin, helospectin, VIP, glucagon and calcitonin. Hepatectomy suppressed the response to glucagon but was without effect on the response to the other peptides. Pancreatectomy and spleenectomy reduced the response to VIP, but was without effect on the response to the other peptides. PACAP-27 stimulated cAMP efflux from the isolated rat tail vein. Hence, it cannot be excluded that blood vessels contribute to the peptide evoked plasma cAMP response in vivo.
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PMID:Neuropeptides of the vasoactive intestinal peptide/helodermin/pituitary adenylate cyclase activating peptide family elevate plasma cAMP in mice: comparison with a range of other regulatory peptides. 133 41

Pituitary adenylate cyclase-activating peptide (PACAP), a novel hypothalamic peptide that has been shown to exist in several tissues including the testis, was examined for its effects on cultured rat Sertoli cells. PACAP stimulates cAMP accumulation in Sertoli cells cultured from 15-day-old rats in the presence or absence of methylisobutylxanthine, a phosphodiesterase inhibitor, and in the presence of pertussis toxin, a blocker of the adenylate cyclase inhibitory pathway. Maximal stimulation, which is 20-40% of that attainable with FSH, occurs at PACAP concentrations of 10 nM: the ED50 is approximately 100 pM. The ability of PACAP to stimulate Sertoli cell cAMP declines with increasing age of donor animals (15-60 days of age) in a fashion similar to the FSH effect. PACAP stimulation of Sertoli cell cAMP accumulation is additive with submaximal, but not maximal, concentrations of FSH or forskolin. PACAP also stimulates the secretion of lactate, estradiol, and inhibin in a concentration-dependent manner. The stimulation of Sertoli cell cAMP accumulation by PACAP is not altered by a vasoactive intestinal peptide antagonist, and vasoactive intestinal peptide alone does not stimulate cAMP accumulation, indicating that PACAP is not acting via vasoactive intestinal peptide receptors. Further experiments are needed to determine whether PACAP is synthesized within the testis and if so, in which cell types; however, the present data clearly demonstrate that PACAP can modulate Sertoli cell function in vitro.
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PMID:A novel hypothalamic peptide, pituitary adenylate cyclase activating peptide, modulates Sertoli cell function in vitro. 133 66

Calcium is necessary for secretion of pituitary hormones. Many of the biological effects of Ca2+ are mediated by the Ca2+-binding protein calmodulin (CaM), which interacts specifically with proteins regulated by the Ca2+-CaM complex. One of these proteins is myosin light chain kinase (MLCK), a Ca2+-calmodulin dependent enzyme that phosphorylates the regulatory light chains of myosin, and has been implicated in motile processes in both muscle and non-muscle tissues. We determined the content and distribution of CaM and CaM-binding proteins in bovine pituitary homogenates, and subcellular fractions including secretory granules and secretory granule membranes. CaM measured by radioimmunoassay was found in each fraction; although approximately one-half was in the cytosolic fraction, CaM was also associated with the plasma membrane and secretory granule fractions. CaM-binding proteins were identified by an 125I-CaM gel overlay technique and quantitated by densitometric analysis of the autoradiograms. Pituitary homogenates contained nine major CaM-binding proteins of 146, 131, 90, 64, 58, 56, 52, 31 and 22 kilodaltons (kDa). Binding to all the bands was specific, Ca2+-sensitive, and displaceable with excess unlabeled CaM. Severe heat treatment (100 degrees C, 15 min), which results in a 75% reduction in phosphodiesterase activation by CaM, markedly decreased 125I-CaM binding to all protein bands. Secretory granule membranes showed enhancement for CaM-binding proteins with molecular weights of 184, 146, 131, 90, and 52,000. A specific, affinity purified antibody to chicken gizzard MLCK bound to the 146 kDa band in homogenates, centrifugal subcellular fractions, and secretory granule membrane. No such binding was associated with the granule contents. The enrichment of MLCK and other CaM-binding proteins in pituitary secretory granule membranes suggest a possible role for CaM and/or CaM-binding proteins in granule membrane function and possibly exocytosis.
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PMID:Distribution of calmodulin and calmodulin-binding proteins in bovine pituitary: association of myosin light chain kinase with pituitary secretory granule membranes. 358 33

Pituitary cells were prepared by enzymatic dispersion and incubated in vitro. To observe the effect of gonadotropin releasing hormone (GnRH) and Ca2+ on the murrel pituitary cyclic 3',5'-AMP (cAMP), cells were dispersed by 0.3% collagenase plus 0.05% trypsin in Earle's minimum essential medium without Ca2+ and a considerably high yield of viable cells were obtained. Addition of a murrel, Channa punctatus, GnRH (cGnRH, 10 micrograms/incubation) to pituitary cell incubation (6 x 10(4) cells/well) containing 4 mM theophylline, a phosphodiesterase (PDE) inhibitor, stimulated cAMP accumulation in the pituitary cell 2.4-fold and its release into the medium about 2-fold as compared to control. The extent of stimulation was greatly increased on addition of Ca2+ (2 mM/incubation) with cGnRH: accumulation 5.8-fold and release 3.7-fold, respectively, in comparison to control. A time-course study with cGnRH (20 micrograms/incubation) plus Ca2+ (2 mM/incubation) on pituitary cell cAMP accumulation showed that the peak of cAMP level was reached at 15 min and remained at the same level until 60 min in the presence of theophylline; this peak was drastically reduced (5-fold) at 30 min in the absence of theophylline, indicating rapid hydrolysis of cAMP by PDE. Ca(2+)-augmented cGnRH stimulatory effect on cAMP accumulation and release could be significantly (P < 0.01) inhibited by verapamil (3 microM/incubation), a specific calcium channel blocker, suggesting requirement of extracellular Ca2+ influx in this process. Calmodulin (CaM), a Ca2+ carrier protein, addition to cGnRH and Ca2+ incubation further augmented the increase of cellular accumulation of cAMP and its release by 39.5 and 45%, respectively, in comparison to cGnRH and Ca2+ (both were statistically significant, P < 0.01). CaM effect could be blocked by calmidazolium (1 microM/incubation), a specific inhibitor of CaM, indicating specificity of the stimulatory action of CaM. Addition of radioiodinated 125I-CaM, in the presence of Ca2+ or cGnRH plus Ca2+ resulted in the binding of 125I-CaM to pituitary cells and to the pellet of the lysed cells. 125I-CaM specifically binds to pituitary cell plasma membrane preparation and saturation of 125I-CaM binding occurred at 9 ng of 125I-CaM. To investigate whether cGnRH plus Ca(2+)-stimulation of pituitary cells cAMP is linked to gonadotropin (GtH) release, similar protocols were followed. It was found that GtH release was augmented to 7-fold by cGnRH plus Ca2+, which was inhibited by verapamil and stimulated by CaM in a similar manner as observed in the case of cAMP.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Gonadotropin releasing hormone stimulation of cyclic 3',5'-AMP in the pituitary cell of a teleost (Channa punctatus, Bloch) requires extracellular calcium: its relationship to gonadotropin release. 778 50

Pituitary adenylate cyclase-activating peptide (PACAP) represents a novel brain-gut peptide with high sequence homology to vasoactive intestinal polypeptide (VIP). Since PACAP has been identified in the human gut, the effect of the two molecular forms PACAP-(1-38) and PACAP-(1-27), the hybrid PACAP-(1-23)VIP-(24-28), and VIP on the contractility of the longitudinal muscle of human sigmoid colon was tested in vitro. All peptides inhibited the spontaneous phasic contractions and relaxed concentration-dependently carbachol-precontracted preparations. The effects of the peptides remained unaffected by tetrodotoxin, by inhibition of phosphodiesterase activity, and by inhibition of nitric oxide synthesis. Apamin reduced only the effects of the PACAP peptides, whereas tetraethylammonium blocked only the effect of VIP. In conclusion, PACAP peptides and VIP mediate their relaxant effects via activation of specific PACAP and VIP receptors coupled to different potassium channels.
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PMID:Pituitary adenylate cyclase-activating peptide is a potent modulator of human colonic motility. 836 18

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

ECL cells are numerous in the acid-producing part of the rat stomach. They are rich in histamine and pancreastatin, a chromogranin A-derived peptide, and they secrete these products in response to gastrin. We have examined how isolated ECL cells respond to a variety of neuromessengers and peptide hormones. Highly purified (85%) ECL cells were collected from rat stomach using repeated counter-flow elutriation and cultured for 48 h before experiments were conducted. The ECL cells responded to gastrin, sulphated cholecystokinin-8 and to high K+ and Ca2+ with the parallel secretion of histamine and pancreastatin. Glycine-extended gastrin was without effect. Forskolin, an activator of adenylate cyclase, induced secretion, whereas isobutylmethylxanthine, a phosphodiesterase inhibitor, raised the basal release without enhancing the gastrin-evoked stimulation. Maximum stimulation with gastrin resulted in the release of 30% of the secretory products. Numerous neuromessengers and peptide hormones were screened for their ability to stimulate secretion and to inhibit gastrin-stimulated secretion. Pituitary adenylate cyclase activating peptide (PACAP)-27 and -38 stimulated secretion of both histamine and pancreastatin with a potency greater than that of gastrin and with the same efficacy. Related peptides, such as vasoactive intestinal peptide, helodermin and helospectin, stimulated secretion with lower potency. The combination of EC100 gastrin and EC50 PACAP produced a greater response than gastrin alone. None of the other neuropeptides or peptide hormones tested stimulated secretion. Serotonin, adrenaline, noradrenaline and isoprenaline induced moderate secretion at high concentrations. Muscarinic receptor agonists did not stimulate secretion, and histamine and selective histamine receptor agonists and antagonists were without effect. This was the case also with GABA, aspartate and glutamate. Somatostatin and galanin, but none of the other agents tested, inhibited gastrin-stimulated secretion. Our results reveal that not only gastrin but also PACAP is a powerful excitant of the ECL cells, that not only somatostatin, but also galanin can suppress secretion, that muscarinic receptor agonists fail to evoke secretion, and that histamine (and pancreastatin) does not evoke autofeedback inhibition.
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PMID:Neurohormonal regulation of histamine and pancreastatin secretion from isolated rat stomach ECL cells. 941 89

In recent years, remarkable progress has been made in the understanding of the pathogenesis of pituitary tumors. Pituitary tumors originate from the uncontrolled proliferation of a single transformed cell in which an initiating event has caused a gain of proliferative function. After the initiation, promoting factors cooperate in the clonal expansion. Common oncogenes, such as ras, are only exceptionally involved. The only activating mutations identified so far are gsp mutations causing the constitutive activation of cAMP pathway. However, gsp-positive adenomas are not associated to a more aggressive tumoral phenotype. The oncogenic potential of gsp mutations is limited by a more rapid degradation of the mutant Gs(alpha) with respect to the wild-type protein, and by a faster removal of cAMP due to increased phosphodiesterase activity. Estrogen-inducible gene sequences with transforming properties (pituitary tumor-transforming gene (PTTG)) have been identified in human pituitary tumors. Human pituitary tumor-transforming gene (hPTTG) is involved both in early pituitary tumorigenesis, as it causes in vitro and in vivo transformation acting as a transcription activator, and in tumor progression, as it regulates the production of basic fibroblast growth factor (bFGF), a potent activator of angiogenesis and mitogenesis. Moreover, a role of cyclin D1 in pituitary tumorigenesis is emerging. The allelic loss of loci for unknown oncosuppressor genes are currently under investigation, while an exceedingly limited role for menin gene and RB1 has been demonstrated for sporadic pituitary tumors. Abnormal methylation that predisposing toward genetic instability may favor the allelic loss or the reduced expression of oncosuppressor genes, is also an emerging field of investigation. Several promoting factors, including the excessive action of physiological stimulators, the defective action of inhibitors, the susceptibility to respond to inappropriate stimuli and the locally produced growth factors, help in tumor progression. The study of homeobox genes that intervene in pituitary cell differentiation may help in expanding our knowledge in pituitary tumor cell genealogy.
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PMID:Genesis of pituitary adenomas: state of the art. 1176 37

Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide that exerts its effects throughout the body by elevating the intracellular amounts of cAMP. In adipocytes, an increased amount of cAMP is associated with increased lipolysis. In this work we evaluated the effects of PACAP38 on triglyceride metabolism in primary rat adipocytes. Stimulation of adipocytes with PACAP (0.1-100 nm) resulted in stimulation of lipolysis to the same extent as isoproterenol. Lipolysis was blocked by 25 microm of the protein kinase A inhibitor H-89 and potentiated in the presence of 10 microm OPC3911, a phosphodiesterase 3 inhibitor. In addition, PACAP38 induced activation of protein kinase A. Insulin efficiently inhibited PACAP38-induced lipolysis in a phosphatidyl inositol 3-kinase and phosphodiesterase 3-dependent manner. Interestingly, we also found that PACAP38, as well as isoproterenol, induced potentiation of lipogenesis in the presence of insulin. These results show that PACAP38 and isoproterenol mediate catabolic as well as anabolic effects in adipocytes, depending on the concentration of insulin present. We speculate that in the early postprandial state and during fasting, when insulin levels are low, PACAP and beta-adrenergic catecholamines induce lipolysis, whereas when higher levels of insulin are present, these agents potentiate the anabolic effect of insulin, i.e. storage of triglycerides.
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PMID:Dual effects of pituitary adenylate cyclase-activating polypeptide and isoproterenol on lipid metabolism and signaling in primary rat adipocytes. 1296 Jan 3


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