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)

To confirm the intracellular signal transduction in regulation of alkaline phosphatase (ALP) activity by calcitonin in kidney tubular cells, effects of several inhibitors of cyclic nucleotide phosphodiesterase (PDE) isoenzymes and cyclic AMP-dependent protein kinase (PKA) on the action of salmon calcitonin in porcine kidney tubular epithelial cells LLC-PK1 were examined. A confluent culture of LLC-PK1 cells was treated with calcitonin and inhibitors in Dulbecco's modified Eagle's medium supplemented with 0.1% bovine serum albumin, and intracellular cyclic AMP content and ALP activity were measured after incubation for 30 min and 48 hr, respectively. Calcitonin and PDE 4 inhibitors increased cyclic AMP level and ALP activity in the cells, and PDE 4 inhibitors synergistically potentiated the effects of calcitonin. Calcitonin induced ALP activation by treatment for the first 1 hr, as well as continuous treatment for 48 hr, while it never increased the enzyme activity just after 1-hr exposure. Rolipram, an inhibitor of PDE 4 isoenzyme, induced ALP activation by itself and in combination with calcitonin by only a long term treatment (48 hr). The activation of ALP by calcitonin and rolipram each alone and in combination was completely abolished by a PKA inhibitor, H-89. These results confirm that calcitonin induces ALP activation through the cyclic AMP-PKA pathway and that PDE 4 isoenzyme is closely associated with the calcitonin-receptor system and plays a major role in hydrolysis of cyclic AMP produced in the kidney tubular cells.
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PMID:Role of phosphodiesterase 4 isoenzyme in alkaline phosphatase activation by calcitonin in porcine kidney LLC-PK1 cells. 954 Dec 82

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

Vasorelaxant effects of calcitonin gene-related peptide (CGRP) are dependent on endothelium-derived nitric oxide (NO) in some arteries. The mechanism involved is still not clear. In the present study, we used NO donors (sodium nitroprusside (SNP) and 6-(2-hydroxy-1-methyl-2-nitrisohydrazino)-N-methyl-1-hyxanamine (NOC-9)), cyclic GMP elevator (brain natriuretic peptide (BNP)) and a selective type III (cyclic GMP-inhibited) phosphodiesterase (PDE) inhibitor 5-(4-acetamidophenyl)pyrazin-2(1H)-one (SK&F94120) to investigate involvement of NO, cyclic GMP and type III PDE in CGRP-induced accumulation of cyclic AMP in cultured rat aortic smooth muscle cells. SNP (10 microM), NOC-9 (10 microM) and BNP (1 microM) all increased intracellular cyclic GMP to similar levels (2- to 2.5-fold above basal) and caused significant enhancement of CGRP (10 nM)-induced cyclic AMP accumulation similar to that caused by 10 microM SK&F 94120. The data are therefore consistent with our hypothesis that the mechanism of endothelium-dependent vasorelaxation effect of CGRP involves cyclic GMP-mediated inhibition of type III PDE and subsequent accumulation of cyclic AMP in smooth muscle cells.
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PMID:Nitric oxide donors enhance calcitonin gene-related peptide-induced elevations of cyclic AMP in vascular smooth muscle cells. 1044 92

Adrenomedullin is a peptide recently isolated from pheochromocytoma that has vasorelaxant and long-lasting hypotensive activities. Plasma levels of adrenomedullin are elevated in patients with congestive heart failure, but the effects of adrenomedullin on the cardiac function are unclear. We, thus, investigated the effects of adrenomedullin on the contraction of rat papillary muscles. We measured the isometric tension and cAMP contents of isolated rat papillary muscles. Adrenomedullin exhibited concentration-dependent inotropic effects. Adrenomedullin also significantly increased intracellular contents of cAMP. Addition of the calcitonin gene-related peptide (CGRP) receptor antagonist inhibited both contractile force and cAMP generation of papillary muscles stimulated by adrenomedullin. The adrenomedullin-induced inotropic effect was further increased in the presence of the phosphodiesterase inhibitor, 3-isobutyl-1-methyl-xanthine (IBMX), while the effect was significantly suppressed by KT5720 and Rp-8-bromoadenosine-3',5'-cyclic monophosphorothioate (Rp-8-Br-cAMPS), protein kinase A inhibitors. These results indicate that adrenomedullin has positive inotropic effects on the heart, at least partially through a cAMP-dependent pathway.
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PMID:Positive inotropic effects of adrenomedullin on rat papillary muscle. 1070 20

A series of xanthine sulfonamides is presented as a class of calcitonin (CT) inducers - a potentially new method for treating diseases associated with postmenopausal bone loss such as osteoporosis. We have found that certain di-n-butylxanthine sulfonamides 4 upregulate CT transcription in a CT-luciferase reporter gene assay (CT-luci) and increase the production and release of CT in a CT secretion/RIA assay (CTS). In addition, these compounds do not have potent PDE4 inhibitory activity as do the related xanthine methylene ketones such as denbufyllene (2). One compound in particular (9) shows a transcription activation ratio (TAR) of 2.1 in CT-luci, a CTS increase of 3.6-fold, and a PDE4 (phosphodiesterase type IV) IC(50) = 4.1 microM. In addition, this compound showed a statistically significant 47% trabecular bone protection in ovariectomized-induced osteopenia (OVX) rats as determined by assay when administered for 4 weeks at 30 mg/kg/day, i. p. by quantitative computed tomography (QCT). When administered p.o., compound 9 shows 50% trabecular bone protection when administered for 3 weeks at 50 mg/kg/day, i.p. This compared with salmon CT which shows 62% trabecular bone protection when administered at 50 IU/kg/day for 4 weeks.
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PMID:Novel and selective calcitonin-inducing agents. 1073 55

Previously we showed that calcitonin gene-related peptide (CGRP), a neuropeptide, inhibited lipopolysaccharide (LPS)-induced tumour necrosis factor-alpha (TNF-alpha) production and increased interleukin (IL)-6 release at low concentrations via activation of the cAMP pathway in mouse peritoneal macrophages (Mphi). In this study we examined whether CGRP could modulate IL-12 release from mouse peritoneal Mphi, and if so, what signal transduction pathway was involved. Mphi were obtained from the peritoneal exudate of male BALB/c mice. The cells were plated on culture dishes at a density of 5 x 105 cells per well and allowed to adhere for 2 hr. After incubation for 24 hr, the Mphi were cultured with 0.1 microg/ml of LPS, alone or together with CGRP (1-1000 nM) for 24 hr. The amount of IL-12 in the cell medium was measured by enzyme-linked immunosorbent assay (ELISA). The results showed that CGRP attenuated LPS-induced IL-12 release in a concentration-dependent manner. Production of IL-12 was decreased from 95.9+/-4.6 to 73.4+/-5.7 pg/ml by 100 nM CGRP. The two cAMP phosphodiesterase (PDE) inhibitors, 3-isobutyl-1-methyl-xanthine (IBMX) and rolipram, significantly potentiated the CGRP response, and the level of IL-12 was further decreased by 28% and 47%, respectively. However, CGRP had no effect on IL-12 production from unstimulated Mphi. The LPS-induced IL-12 release from Mphi could also be reduced by forskolin, an activator of adenylate cyclase, and 8-Br-cAMP, an analogue of cAMP. Using the reverse transcription-polymerase chain reaction (RT-PCR), we found that CGRP also decreased the LPS-induced IL-12 p40 mRNA levels. Furthermore, pretreatment with H89 (0.1 microM or 1 microM), an inhibitor of cAMP-dependent protein kinase, diminished CGRP effects, IL-12 production and gene expression. These data suggest that LPS-induced IL-12 release and gene expression were attenuated by CGRP via an activated cAMP-protein kinase A (PKA) pathway in mouse peritoneal Mphi.
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PMID:Calcitonin gene-related peptide inhibits lipopolysaccharide-induced interleukin-12 release from mouse peritoneal macrophages, mediated by the cAMP pathway. 1101 54

Recent researches suggest that adrenomedullin (ADM) and calcitonin gene-related peptide (CGRP) bind to the same calcitonin receptor-like receptors (CRLR), with receptor specificity being determined by a receptor activity-modifying protein (RAMP). Our objective was to explore the significance of CRLR/RAMP hypothesis in cardiovascular tissues through experiments on the phenomenon of desensitization of both ADM and CGRP receptors using cultured rat aortic vascular smooth muscle cells (VSMCs). VSMCs were incubated for 20 min either in serum-free medium (SFM) alone or in the SFM containing vasoactive agonist [10(-8) mol/L ADM, CGRP and proadrenomedullin (PAMP)]. Cells were washed twice and incubated for another 20 min in SFM containing a repetitive agonist ADM or CGRP and 0.5 mmol/L isobutyryl methylxant (an inhibitor of phosphodiesterase). VSMCs were harvested and assayed for cAMP. Exposure of VSMCs to ADM, CGRP, or PAMP alone increased intracellular cAMP generation by 191% (P < 0.01), 385% (P < 0.01) and 67% (P < 0.05), respectively, compared with SFM group. Pre-treatment of VSMCs to ADM or CGRP decreased cAMP generation in response to subsequent stimulation with CGRP by 44% (P < 0.05) and 48% (P < 0.01), respectively. Pre-treatment of VSMCs with 100 nmol/L H-89, a protein kinase A (PKA) inhibitor, abolished the desensitization of CGRP-acting receptor, implying that this desensitization was mediated through PKA. In contrast, there was no attenuation in cAMP response to stimulation with ADM by pre-exposure to ADM or CGRP. Identical results were seen with or without PKA inhibition by H-89. Pre-exposure of VSMCs to PAMP resulted in no change in cAMP generation in response to subsequent stimulation with ADM or CGRP. These results indicate that ADM receptors do not desensitize in VSMCs in contrast to CGRP-receptors, which are desensitized by pre-exposure to ADM or CGRP. These data also suggest that the desensitization phenomenon of ADM is different from that of CGRP.
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PMID:Desensitization of adrenomedullin and calcitonin gene-related peptide receptors in vascular smooth muscle cells--effects of receptor activity-modifying protein. 1183 26

A series of pyrazolo[4,3-d]pyrimidine sulfonamides and pyrazolo[3,4-d]pyrimidine sulfonamides have been synthesized. These compounds increase transcription of a calcitonin-luciferase promoter and production of cellular calcitonin in a calcitonin-secretion/RIA assay with minimized phosphodiesterase type 4 inhibitory activity at 30 microM as compared to structurally related xanthine methylene ketones such as denbufyllene. These two series are notable examples of small molecules that act as CT-inducers, a method to potentially treat bone loss diseases.
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PMID:Pyrazolopyrimidine-2,4-dione sulfonamides: novel and selective calcitonin inducers. 1201 73

The action of calcitonin gene-related pepide (CGRP) was studied on c-fos gene expression in rat astrocyte cultures. A strong and transient increase in c-fos mRNA was observed in cultured astrocytes after treatment with CGRP. Quantitative Northern blot analysis revealed an increase of c-fos mRNA within 15 min, a peak after 30 min with a 10 - 15 fold increase over unstimulated cells and a subsequent decline. Induction of the c-fos gene by CGRP was concentration-dependent, half maximal stimulation of c-fos mRNA being obtained with 100 nM CGRP. The CGRP effect appeared to be mediated by a CGRP receptor and calcitonin was found to mimic only weakly the action of CGRP on cultured astrocytes. Calcitonin transiently induced c-fos gene expression with a similar time course to CGRP, but its effect was much less pronounced. Agents affecting the intracellular cyclic AMP level, forskolin and Ro 20-1724, stimulated c-fos mRNA in a strong and transient fashion with a temporal sequence similar to the response to CGRP. Further, the phosphodiesterase inhibitor Ro 20-1724 potentiated the action of CGRP on c-fos mRNA induction, suggesting a role for cyclic AMP in the action of CGRP. The present results indicate that CGRP may play a physiological role as a regulator of astrocyte gene expression.
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PMID:Calcitonin Gene-related Peptide Stimulates the Induction of c-fos Gene Expression in Rat Astrocyte Cultures. 1210 78

Results from basic research implicate a role for bioactive peptides in controlling the mammalian lower urinary tract. Although various peptides are assumed to be involved in the potentiaton or inhibition of cholinergic or purinergic activity in the urinary bladder, there is still much controversy regarding the mode of action and functional significance of such peptides in detrusor smooth muscle. Thus, we evaluated the functional effects of atrial natriuretic peptide (ANP), calcitonin gene related peptide (CGRP), endothelin 1 (ET-1), substance P (SP) and vasoactive intestinal polypeptide (VIP) on isolated strip preparations of human detrusor smooth muscle and determined the presence of those peptides in the human detrusor by means of immunohistochemistry. The effects of peptides on isometric tension of isolated detrusor strip preparations and on tissue levels of cyclic nucleotides cAMP and cGMP were compared to those of adenylyl cyclase activator forskolin (F), nitric oxide donor Na(+)-nitroprusside (SNP) and non-specific phosphodiesterase (PDE) inhibitor papaverine (P). The effects of the compounds on isometric tension of isolated human detrusor smooth muscle were examined using the organ bath technique. To determine time- and dose-dependent effects on cyclic nucleotide levels, bladder strips were exposed to increasing doses of F, SNP, P, ANP, CGRP and VIP, then rapidly frozen in liquid nitrogen and homogenised in the frozen state. cAMP and cGMP were extracted and assayed using specific radioimmunoassays. The presence of peptides was investigated by light microscopy using the Avidin-Biotin-Complex (ABC) method. F, P and VIP most effectively reversed the carbachol-induced tension of isolated human detrusor strips. Relaxing effects of ANP, CGRP and SNP were negligible. In contrast, ET-1 and SP elicited dose-dependent contractions of the tissue. The relaxing effects of F, P and VIP were accompanied by an increase in cAMP and cGMP levels, respectively. Light microscopy revealed positive immunostaining for CGRP, ET 1, VIP and SP in sections of the detrusor muscle coat. Our results suggest a possible importance of ET 1, SP and VIP in regulating detrusor smooth muscle contraction and relaxation. Even if a peptide is not synthesised, stored or released in a smooth muscle tissue and is, therefore, unable to reach its target cells under physiologic conditions, a functional effect on the tissue might be mediated by peptide-binding to specific cell surface receptors.
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PMID:Possible role of bioactive peptides in the regulation of human detrusor smooth muscle - functional effects in vitro and immunohistochemical presence. 1221 55


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