Academic literature on the topic 'CAMP/cGMP'
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Journal articles on the topic "CAMP/cGMP"
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Jiang, Hang, John B. Shabb, and Jackie D. Corbin. "Cross-activation: overriding cAMP/cGMP selectivities of protein kinases in tissues." Biochemistry and Cell Biology 70, no. 12 (1992): 1283–89. http://dx.doi.org/10.1139/o92-175.
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cAMP- and cGMP-dependent protein kinases are homologous proteins and are predicted to exhibit very similar three-dimensional structures. Their cyclic nucleotide binding domains share a high degree of amino acid sequence identity. cAMP- and cGMP-dependent protein kinases are activated relatively specifically by cAMP and cGMP, respectively; and a single alanine–threonine difference between cAMP- and cGMP-binding domains partially accounts for this specificity. Thus, it would be expected that cAMP and cGMP mediate separate physiological effects. However, owing in part to the lack of absolute specificity of either enzyme and to the relatively high level of cAMP or cGMP in certain tissues, it is also possible that either cyclic nucleotide could cross-activate the other kinase. Increases in either cAMP or cGMP cause pig coronary artery relaxation. However, only cGMP-dependent protein kinase specific cyclic nucleotide analogues are very effective in causing relaxation, and cAMP elevation in arteries treated with isoproterenol or forskolin activates cGMP-dependent protein kinase, in addition to cAMP-dependent protein kinase. Conversely, increases in either cAMP or cGMP cause Cl− secretion in T-84 colon carcinoma cells, and the cGMP level in T-84 cells can be elevated sufficiently by bacterial enterotoxin to activate cAMP-dependent protein kinase. These results imply specific regulation of cAMP- and cGMP-dependent protein kinases by the respective cyclic nucleotides, but either cyclic nucleotide is able to cross-activate the other kinase in certain tissues.Key words: cGMP, cAMP, smooth muscle relaxation, protein phosphorylation.
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Inamura, Kouhei, Makoto Kashiwayanagi, and Kenzo Kurihara. "Effects of cGMP and sodium nitroprusside on odor responses in turtle olfactory sensory neurons." American Journal of Physiology-Cell Physiology 275, no. 5 (1998): C1201—C1206. http://dx.doi.org/10.1152/ajpcell.1998.275.5.c1201.
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The effects of cGMP and sodium nitroprusside (SNP) on odor responses in isolated turtle olfactory neurons were examined. The inward current induced by dialysis of a mixture of 1 mM cAMP and 1 mM cGMP was similar to that induced by dialysis of 1 mM cAMP or 1 mM cGMP alone. After the neurons were desensitized by the application of 1 mM cGMP, 3 mM 8-(4-chlorophenylthio)-cAMP, a membrane-permeable cAMP analog, did not elicit any current, indicating that both cAMP and cGMP activated the same channel. Extracellular application of SNP, a nitric oxide (NO) donor, evoked inward currents in a dose-dependent manner. However, application of SNP did not induce any currents after desensitization of the cGMP-induced currents, suggesting that SNP-induced currents are mediated via the cGMP-dependent pathway. Application of the cAMP-producing odorants to the neurons induced a large inward current even after neurons were desensitized to a high concentration of cGMP or SNP. These results suggest that the transduction pathway independent of cAMP, cGMP, and NO also contributes to the generation of odor responses in addition to the cAMP-dependent pathway.
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Xu, Hao-Liang, Hailemariam M. Wolde, Vitaliy Gavrilyuk, Verna L. Baughman, and Dale A. Pelligrino. "cAMP modulates cGMP-mediated cerebral arteriolar relaxation in vivo." American Journal of Physiology-Heart and Circulatory Physiology 287, no. 6 (2004): H2501—H2509. http://dx.doi.org/10.1152/ajpheart.00319.2004.
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No studies have specifically addressed whether cAMP can influence nitric oxide (NO)/cGMP-induced cerebral vasodilation. In this study, we examined whether cAMP can enhance or reduce NO-induced cerebral vasodilation in vivo via interfering with cGMP efflux or through potentiating phosphodiesterase 5 (PDE5)-mediated cGMP breakdown, respectively, in cerebral vascular smooth muscle cells (CVSMCs). To that end, we evaluated, in male rats, the effects of knockdown [via antisense oligodeoxynucleotide (ODN) applications] of the cGMP efflux protein multidrug resistance protein 5 (MRP5) and PDE5 inhibition on pial arteriolar NO donor [ S-nitroso- N-acetyl penicillamine (SNAP)]-induced dilations in the absence and presence of cAMP elevations via forskolin. Pial arteriolar diameter changes were measured using well-established protocols in anesthetized rats. In control (missense ODN treated) rats, forskolin elicited a leftward shift in the SNAP dose-response curves (∼50% reduction in SNAP EC50). However, in MRP5 knockdown rats, cAMP increases were associated with a substantial reduction in SNAP-induced vasodilations (reflected as a significant 35–50% lower maximal response). In the presence of the PDE5 inhibitor MY-5445, the repression of the NO donor response accompanying forskolin was prevented. These findings suggest that cAMP has opposing effects on NO-stimulated cGMP increases. On the one hand, cAMP limits CVSMC cGMP loss by restricting cGMP efflux. On the other, cAMP appears to enhance PDE5-mediated cGMP breakdown. However, because increased endogenous cAMP seems to potentiate NO/cGMP-induced arteriolar relaxation when MRP5 expression is normal, the effect of cAMP to reduce cGMP efflux appears to predominate over cAMP stimulation of cGMP hydrolysis.
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Hasegawa, K., H. Kikuchi, S. Ishizaki, et al. "Simple fluctuation of Ca2+ elicits the complex circadian dynamics of cyclic AMP and cyclic GMP in Paramecium." Journal of Cell Science 112, no. 2 (1999): 201–7. http://dx.doi.org/10.1242/jcs.112.2.201.
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The circadian dynamics of cyclic adenosine 3′,5′-monophosphate (cAMP) and cyclic guanosine 3′,5′-monophosphate (cGMP) were simulated in Paramecium multimicronucleatum. The mathematical functions determined closely mimic the Ca2+ dependence of adenylate cyclase (AC) and guanylate cyclase (GC) activities as documented in P. tetraurelia. Patterns of cAMP concentration ([cAMP]), cGMP concentration ([cGMP]), and the ratio [cGMP]/[cAMP] were calculated with respect to Ca2+ concentrations ([Ca2+]) fluctuating sinusoidally with a period of 24 hours at three different levels: low, medium, and high. The functions displayed varying patterns of [cAMP] characteristic for [Ca2+] fluctuating at each level, while patterns of [cGMP] and [cGMP]/[cAMP] almost paralleled [Ca2+] fluctuations. Similar patterns were observed for actual [cAMP] and [cGMP] measured during the light/dark cycle in P. multimicronucleatum, grown in axenic media additionally containing [Ca2+] at 25 (low), 100 (medium), or 400 (high) microM, respectively. The coincidence between simulated and measured fluctuations of [cAMP] and [cGMP] suggests that the circadian fluctuations of intracellular [Ca2+] primarily stimulate activities of AC and GC via their different degrees of Ca2+ dependence, which are ultimately responsible for the circadian spatiotemporal organization of various physiological functions in Paramecium.
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Stangherlin, Alessandra, and Manuela Zaccolo. "cGMP–cAMP interplay in cardiac myocytes: a local affair with far-reaching consequences for heart function." Biochemical Society Transactions 40, no. 1 (2012): 11–14. http://dx.doi.org/10.1042/bst20110655.
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cAMP and cGMP signalling pathways are common targets in the pharmacological treatment of heart failure, and often drugs that modulate the level of these second messengers are simultaneously administered to patients. cGMP can potentially affect cAMP levels by modulating the activity of PDEs (phosphodiesterases), the enzymes that degrade cyclic nucleotides. This biochemical cross-talk provides the means for drugs that increase cGMP to concomitantly affect cAMP signals. Recent studies using FRET (fluorescence resonance energy transfer) reporters and real-time imaging show that, in cardiac myocytes, the interplay between cGMP and cAMP has different outcomes depending on the specific location where the cross-modulation occurs. cGMP can either increase or decrease the cAMP response to catecholamines, based on the cyclase that generates it and on the PDEs associated with each subcellular compartment. cGMP-mediated modulation of cAMP signals has functional relevance as it affects protein phosphorylation downstream of protein kinase A and myocyte contractility. The physical separation of positive and negative modulation of cAMP levels by cGMP offers the previously unrecognized possibility to selectively modulate local cAMP signals to improve the efficacy of therapy.
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DICKINSON, Natalie T., Elliott K. JANG, and Richard J. HASLAM. "Activation of cGMP-stimulated phosphodiesterase by nitroprusside limits cAMP accumulation in human platelets: effects on platelet aggregation." Biochemical Journal 323, no. 2 (1997): 371–77. http://dx.doi.org/10.1042/bj3230371.
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cGMP enhances cAMP accumulation in platelets via cGMP-inhibited phosphodiesterase (PDE3) [Maurice and Haslam (1990) Mol. Pharmacol. 37, 671–681]. However, cGMP might also limit cAMP accumulation by activating cGMP-stimulated phosphodiesterase (PDE2). We therefore evaluated the role of PDE2 in human platelets by using erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) to inhibit this enzyme selectively. IC50 values for the inhibition of platelet PDE2 by EHNA, with 10 μM cAMP as substrate in the absence and in the presence of 1 μM cGMP, were 15 and 3 μM respectively. Changes in platelet cyclic [3H]nucleotides were measured after prelabelling with [3H]adenine and [3H]guanine. Nitroprusside (NP) caused concentration-dependent increases in [3H]cGMP and a biphasic increase in [3H]cAMP, which was maximal at 10 μM (49±6%) and smaller at 100 μM (32±6%) (means±S.E.). In the presence of EHNA (20 μM), which had no effects alone, NP caused much larger increases in platelet [3H]cAMP (125±14% at 100 μM). EHNA also enhanced [3H]cGMP accumulation at high NP concentrations. In accord with these results, EHNA markedly potentiated the inhibition of thrombin-induced platelet aggregation by NP. The roles of cAMP and cGMP in this effect were investigated by using 2´,5´-dideoxyadenosine to inhibit adenylate cyclase. This compound decreased the accumulation of [3H]cAMP but not that of [3H]cGMP, and diminished the inhibition of platelet aggregation by NP with EHNA. We conclude that much of the effect of NP with EHNA is mediated by cAMP. Lixazinone (1 μM), a selective inhibitor of PDE3, increased platelet [3H]cAMP by 177±15%. This increase in [3H]cAMP was markedly inhibited by NP; EHNA blocked this effect of NP. Parallel studies showed that NP suppressed the inhibition of platelet aggregation by lixazinone. EHNA enhanced the large increases in [3H]cAMP seen with 20 nM prostacyclin (PGI2), but had no effect with 1 nM PGI2. NP and 1 nM PGI2 acted synergistically to increase [3H]cAMP, an effect attributable to the inhibition of PDE3 by cGMP; EHNA greatly potentiated this synergism. In contrast, NP decreased the [3H]cAMP accumulation seen with 20 nM PGI2, an effect that was blocked by EHNA. The results show that, provided that cGMP is present, PDE2 plays a major role in the hydrolysis of low cAMP concentrations and restricts any increases in cAMP concentration and decreases in platelet aggregation caused by the inhibition of PDE3. At high cAMP, PDE2 plays the major role in cAMP breakdown, whether cGMP is present or not.
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Dembinsky, A., H. Rubin, and S. Ravid. "Chemoattractant-mediated increases in cGMP induce changes in Dictyostelium myosin II heavy chain-specific protein kinase C activities." Journal of Cell Biology 134, no. 4 (1996): 911–21. http://dx.doi.org/10.1083/jcb.134.4.911.
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Myosin II heavy chain (MHC)-specific protein kinase C (MHC-PKC) isolated from the ameba, Dictyostelium discoideum, regulates myosin II assembly and localization in response to the chemoattractant cAMP (Abu-Elneel et al. 1996. J. Biol. Chem. 271:977- 984). Recent studies have indicated that cAMP-induced cGMP accumulation plays a role in the regulation of myosin II phosphorylation and localization (Liu, G., and P. Newell. 1991. J. Cell. Sci. 98: 483-490). This report describes the roles of cAMP and cGMP in the regulation of MHC-PKC membrane association, phosphorylation, and activity (hereafter termed MHC-PKC activities). cAMP stimulation of Dictyostelium cells resulted in translocation of MHC-PKC from the cytosol to the membrane fraction, as well as increasing in MHC-PKC phosphorylation and in its kinase activity. We present evidence that MHC is phosphorylated by MHC-PKC in the cell cortex which leads to myosin II dissociation from the cytoskeleton. Use of Dictyostelium mutants that exhibit aberrant cAMP-induced increases in cGMP accumulation revealed that MHC-PKC activities are regulated by cGMP. Dictyostelium streamer F mutant (stmF), which produces a prolonged peak of cGMP accumulation upon cAMP stimulation, exhibits prolonged increases in MHC-PKC activities. In contrast, Dictyostelium KI-10 mutant that lacks the normal cAMP-induced cGMP response, or KI-4 mutant that shows nearly normal cAMP-induced cGMP response but has aberrant cGMP binding activity, show no changes in MHC-PKC activities. We provide evidence that cGMP may affect MHC-PKC activities via the activation of cGMP-dependent protein kinase which, in turn, phosphorylates MHC-PKC. The results presented here indicate that cAMP-induced cGMP accumulation regulates myosin II phosphorylation and localization via the regulation of MHC-PKC.
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Krizhanovsky, Valery, Orly Agamy, and Michael Naim. "Sucrose-stimulated subsecond transient increase in cGMP level in rat intact circumvallate taste bud cells." American Journal of Physiology-Cell Physiology 279, no. 1 (2000): C120—C125. http://dx.doi.org/10.1152/ajpcell.2000.279.1.c120.
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Initial sweet taste transduction is expected to occur in the subsecond time range. We demonstrate a rapid and transient (75–250 ms) increase of cGMP (but not cAMP) level in rat intact circumvallate taste cells after stimulation by sucrose. This rapid increase does not occur in nonsensory epithelial cells. Pretreatment with a nonspecific phosphodiesterase (PDE) inhibitor (IBMX), a specific cAMP-PDE4 inhibitor (denbufylline), or an adenylyl cyclase activator (forskolin) all increased basal cAMP and abolished the sucrose-stimulated cGMP increase at 150 ms. Pretreatment with a soluble guanylyl cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) reduced, whereas a specific cGMP-PDE inhibitor (zaprinast) abolished, the sucrose-stimulated cGMP increase. It is proposed that cGMP is involved in the initial stage of sugar taste transduction and that cGMP is more significant than cAMP at this stage. Activation of soluble guanylyl cyclase and inhibition of cGMP-PDE may be involved in the transient elevation of cGMP in response to sucrose stimulation. Moreover, it appears that cAMP level must remain low for sucrose to stimulate an increase in cGMP.
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Segal, J. "Opposite regulatory effects of cAMP and cGMP on sugar uptake in rat thymocytes." American Journal of Physiology-Endocrinology and Metabolism 252, no. 5 (1987): E588—E594. http://dx.doi.org/10.1152/ajpendo.1987.252.5.e588.
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The present study provides several lines of evidence which indicate that in the rat thymocyte adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5-cyclic monophosphate (cGMP) induce opposing regulatory effects on 2-deoxyglucose (2-DG) uptake; cAMP is stimulatory, whereas cGMP is inhibitory. First, the cyclic nucleotide analogues dibutyryl cAMP (dBcAMP) and dibutyryl cGMP (dBcGMP) produced a dose-related increase and decrease in thymocyte 2-DG uptake, respectively. Second, 3,5,3'-triiodo-L-thyronine (T3) and epinephrine, which increased cellular cAMP concentration but had no effect on cellular cGMP concentration, increased 2-DG uptake in the rat thymocyte. Third, dBcGMP inhibited the stimulatory effects of dBcAMP, T3, and epinephrine on thymocyte 2-DG uptake. Fourth, prostaglandin E1 and the inhibitors of the cyclic nucleotide phosphodiesterases, 3-isobutyl-1-methylxanthine, theophylline, and caffeine, all increased both cellular cAMP and cGMP concentration but had no effect on 2-DG uptake. Insulin did not change cellular cAMP and cGMP concentration, but produced a dose-related increase in 2-DG uptake by the rat thymocyte. From these results I have concluded that in the rat thymocyte cAMP and cGMP produce opposite effects on sugar uptake and that the effect of certain, but not all, agents on thymocyte sugar uptake results from their modulation of cellular cAMP and cGMP concentration.
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Stricker, Stephen A. "Inhibition of germinal vesicle breakdown by antioxidants and the roles of signaling pathways related to nitric oxide and cGMP during meiotic resumption in oocytes of a marine worm." REPRODUCTION 143, no. 3 (2012): 261–70. http://dx.doi.org/10.1530/rep-11-0358.
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In mammalian oocytes, cAMP elevations prevent the resumption of meiotic maturation and thereby block nuclear disassembly (germinal vesicle breakdown (GVBD)), whereas nitric oxide (NO) and its downstream mediator cGMP can either inhibit or induce GVBD. Alternatively, some invertebrate oocytes use cAMP to stimulate, rather than inhibit, GVBD, and in such cases, the effects of NO/cGMP signaling on GVBD remain unknown. Moreover, potential interactions between NO/cGMP and AMP-activated kinase (AMPK) have not been assessed during GVBD. Thus, this study analyzed intraoocytic signaling pathways related to NO/cGMP in a marine nemertean worm that uses cAMP to induce GVBD. For such tests, follicle-free nemertean oocytes were stimulated to mature by seawater (SW) and cAMP elevators. Based on immunoblots and NO assays of maturing oocytes, SW triggered AMPK deactivation, NO synthase (NOS) phosphorylation, and an NO elevation. Accordingly, SW-induced GVBD was blocked by treatments involving the AMPK agonist AICAR, antioxidants, the NO scavenger carboxy-PTIO, NOS inhibitors, and cGMP antagonists that target the NO-stimulated enzyme, soluble guanylate cyclase (sGC). Conversely, SW solutions combining NO/cGMP antagonists with a cAMP elevator restored GVBD. Similarly, AICAR plus a cAMP-elevating drug reestablished GVBD while deactivating AMPK and phosphorylating NOS. Furthermore, sGC stimulators and 8-Br-cGMP triggered GVBD. Such novel results indicate that NO/cGMP signaling can upregulate SW-induced GVBD and that cAMP-elevating drugs restore GVBD by overriding the inhibition of various NO/cGMP downregulators, including AMPK. Moreover, considering the opposite effects of intraoocytic cAMP in nemerteans vs mammals, these data coincide with previous reports that NO/cGMP signaling blocks GVBD in rats.
Dissertations / Theses on the topic "CAMP/cGMP"
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Schobesberger, Sophie. "Changes in cardiomyocyte structure and cAMP/cGMP signalling during heart failure." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/34341.
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The contractile function of the heart depends on efficient β adrenergic receptor (βAR) signalling which involves cycling nucleotides as second messengers. Correct secondary messenger signalling is only possible in healthy, well structured cardiac myocytes. Of the three βAR subtypes present in human cardiomyocytes β1AR and β2AR classically signal via 3'-5' cyclic adenosine monophosphate (cAMP) to regulate contraction after catecholamine administration, whereby the second isoform may also be cardioprotective. The far less characterised β3AR has been controversially associated to both increasing contraction through cAMP and protecting the heart through 3'-5' cyclic guanosine monophosphate (cGMP) signalling. During the progression of heart failure following myocardial infarction (MI) both the normal cell structure and the regulation of cAMP and cGMP signalling are changed. This happens in part due to changes in catecholaminergic stimulation of the βARs and in mechanical load, as well as due to a progressive development of hypertrophy. Some of the alterations initially appear to be of a compensatory nature but escalate into HF by worsening cardiomyocyte function and cell survival. The work presented here (1) investigates the structural integrity of healthy, isolated, single cardiomyocytes by looking at the surface topography via Scanning Ion Conductance Microscopy (SICM) imaging and by examining the internal Transverse Axial Tubule (TAT) network via confocal imaging; (2) elucidates the cyclic nucleotide response to catecholamine stimulation following either global (in the solution) or local (in the SICM pipette) stimulation of either β2ARs or β3ARs and measuring either cAMP or cGMP levels via Förster Resonance Energy Transfer (FRET) sensors in a combined FRET/SICM imaging setup; (3) determines how both the structure and β2AR and β3AR dependent second messenger signalling change in a progressive rat model of HF 4, 8 and 16 weeks after the induction of chronic MI. The major findings of the presented work are as follows: In control cardiomyocytes the structure is highly intricate with regular Z-grooves and crest areas. In MI cells the normal suface topography progressively deteriorates, with the eventual disappearance of Z-grooves by week 16, which correlates with the disorganisation of the cardiomyocyte's internal transverse axial tubule (TAT) network of T-tubules emanating from the cell surface and traversing into the cell centre. This is accompanied by the gradual redistribution of β2ARs from their normal position inside the T-tubules to the unstructured areas on the cardiomyocyte membrane. The regularity and density of the TAT network is already severely compromised at 4 weeks post MI; at the same time a significant drop in the expression of the structural protein Junctophilin 2 (JPH2) occurs. At 4 and 8 weeks post MI a potentially compensatory increase in the number of longitudinal elements takes place which was no longer detectable at 16 weeks. The production of cAMP following local stimulation of β2ARs in the T-tubule openings was already suppressed at 4 weeks post MI and a β2AR response becomes detectable after local stimulation at the cell crests (areas between Z-grooves) at 8 weeks post MI. At 16 weeks post MI the β2AR-dependent cAMP level following both global and local stimulations was reduced due to an overall decrease in the adenylate cyclase (AC) activity. The production of the second cyclic nucleotide, cGMP, following β3AR stimulation is evident in control cells and to a significantly lesser extent in myocytes isolated from hearts at the end stage of HF. These β3AR-cGMP levels were degraded mainly by phosphodiesterases (PDE) 2 and 5. Local stimulation through the SICM pipette reveals that functional β3ARs are primarily localized inside T-tubules in control cells but redistribute equally in between T-tubules and crests in cells isolated from failing hearts. To improve the accuracy and reliability of local application of agonists via the SICM nanopipette voltage was applied to the pipette, as opposed to previously employed displacement of the liquid in the pipette via air pressure. Mathematical modelling served to determine the correct settings for this voltage driven application. It shows that the SICM nanopipette can reliably and precisely unload the βAR agonist ISO onto the nanoscale structure of cardiomyocytes via voltage.
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Assender, Jean W. "Control of vascular smooth muscle cell proliferation by cyclic nucleotides." Thesis, Cardiff University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.389966.
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Janßen, Julia Annika. "In vivo FLIM-FRET as a novel technique to assess cAMP and cGMP in the intact zebrafish heart." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2018. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-232452.
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Introduction: 23 million patients worldwide suffer from heart failure. These patients depend on cardiac research, because cardiac research enables the development of new therapeutic strategies and –targets. In cardiomyocytes, the compartmentalization of cAMP and cGMP depends on many factors. T-tubuli and PDEs are responsible for the division of cells in microdomains in which localized and specific cAMP and cGMP-signaling occurs. The aim of this thesis was to develop a method to answer the open questions that remain about the physiological and pathophysiological significance of cAMP/cGMP compartmentalization. Methods: I used the zebrafish as a model, because the transparency of zebrafish larvae enabled non-invasive fluorescent imaging in cardiomyocytes in the living animal. I cloned the Fluorescence Resonance Energy Transfer (FRET) sensors EPAC1-camps for cAMP and cGi500 for cGMP and injected them into zebrafish fertilized embryos. Then I used the F0 generation for Fluorescence Lifetime Imaging (FLIM) -FRET-measurements of cAMP and cGMP. Ca2+ is an important downstream mediator of cAMP and cGMP, because Ca2+ regulates cardiac contraction. Therefore, I also cloned the Ca2+ sensor GCaMP6 and used the dye Fluo-4 AM to include intracellular Ca2+ in the imaging. Results: The cloned sensors for cAMP, cGMP and Ca2+ were successfully injected into the zebrafish and showed expression in individual cardiomyocytes. I developed a protocol to mount the living zebrafish embryos and to measure intracellular cAMP and cGMP with FLIM-FRET in vivo with high spatial resolution. I characterized the sensors in their functionality by showing that the sensors react to changes in intracellular concentrations of cAMP and cGMP. The results of this study include evidence that zebrafish have mechanisms that lead to cAMP/cGMP compartmentalization in the absence of T-tubuli, and these mechanisms keep compartmentalization constant even under extreme cAMP or cGMP increasing drug treatment. Furthermore, I imaged intracellular Ca2+ by confocal microscopy and developed a protocol to use Fluo-4 AM for Ca2+ imaging. Conclusion: The method used in this thesis should allow the investigation of subcellular cAMP/cGMP compartmentalization and Ca2+ and to subsequently answer open questions in the field, for example whether a change of cAMP compartmentalization leads to the pathological phenotypes of cardiac disease or if a changed compartmentalization of cAMP in cardiac disease influences Ca2+ concentrations and therefore contraction. Additionally, this method can be used to learn more about cAMP, cGMP und Ca2+ during regeneration in the heart, because the zebrafish cardiomyocytes can regenerate<br>Einleitung: Weltweit sind mehr als 23 Millionen unter Herzinsuffizienz leidende Patienten auf die kardiologische Grundlagenforschung angewiesen, da diese die Voraussetzung für eine bessere Versorgung durch adaptierte und neue Behandlungswege schafft. In Kardiomyozyten hängt die Kompartimentierung von cAMP und cGMP von vielen Faktoren ab. T-Tubuli und PDEs werden unter anderem für die Aufteilung der Zellen in Mikrodomänen, in denen lokalisierte und spezifische cAMP- und cGMP-Signalgebung stattfinden kann, verantwortlich gemacht. Das Ziel dieser Arbeit war die Etablierung einer Methode, mithilfe derer offene Fragen bezüglich der physiologischen und insbesondere der pathophysiologischen Relevanz der cAMP- und cGMP Kompartimentierung beantwortet werden können. Methode: Als Modell diente der Zebrafisch, da die Transparenz von Zebrafisch Embryonen eine nicht-invasive Bildgebung von Fluoreszenz in Kardiomyozyten im lebenden Tier ermöglicht. Dafür klonierte ich die Förster Resonance Energy Transfer (FRET) -Sensoren EPAC1-camps als cAMP-Sensor und cGi500 als cGMP-Sensor und injizierte diese in befruchtete Zebrafisch Embryonen. Anschließend benutzte ich die F0-Generation für Fluorescence Lifetime Imaging (FLIM) -FRET-Messungen von cAMP und cGMP. Da Ca2+ als wichtiger downstream Mediator von cAMP und cGMP die kardiale Kontraktion reguliert, klonierte ich außerdem den Ca2+-Sensor GCaMP6 und benutzte den Farbstoff Fluo-4 AM, um intrazelluläres Ca2+ darzustellen. Ergebnisse: Die klonierten Sensoren für cAMP, cGMP und Ca2+ konnten erfolgreich in den Zebrafisch injiziert werden und zeigten alle Expression in einzelnen Kardiomyozyten. Ich entwickelte ein Protokoll, dass die Fixierung von lebenden Zebrafisch Embryonen und nachfolgender Bildgebung von cAMP und cGMP mit hoher zellulärer Auflösung mit FLIM-FRET in vivo erlaubte. Ich konnte eine funktionelle Charakterisierung der Sensoren durchführen, indem ich zeigte, dass sie auf Konzentrationsänderungen von intrazellulärem cAMP und cGMP reagieren sowie zeigen, dass Zebrafische trotz fehlender T-Tubuli eine signifikante cAMP- und cGMP Kompartimentierung aufweisen, auch unter extremen Bedingungen nach Gabe von cAMP/cGMP stimulierenden Substanzen in hoher Dosierung. Ich konnte zudem subzelluläres Ca2+ durch konfokale Mikroskopie bildgebend darstellen und entwickelte ein Protokoll, um mit Fluo-4 AM eine schnelle Möglichkeit zu haben, Ca2+ mit in die Messungen einzubeziehen. Ausblick: Die in dieser Arbeit benutzte Methode bietet eine gute Möglichkeit, subzelluläre cAMP- und cGMP-Kompartimentierung und Ca2+ zu untersuchen und damit zum Beispiel die Fragen zu beantworten, ob eine veränderte cAMP/cGMP Kompartimentierung zu Herzkrankheiten wie Hypertrophie führt oder ob eine veränderte cAMP Kompartimentierung den zellulären Ca2+ Haushalt und damit die kardiale Kontraktion beeinflusst. Darüber hinaus kann das von mir etablierte Protokoll dazu genutzt werden, mehr über cAMP, cGMP und Ca2+ während der Regeneration im Herzen zu lernen, da der Zebrafisch über ausgeprägte Regenerationsfähigkeiten verfügt
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Kühn, Rainer. "Untersuchungen zur Bedeutung der cAMP- und cGMP- abhängigen Signaltransduktion in der Kontrolle der glatten Muskulatur des humanen Ureters." Diss., lmu, 2008. http://nbn-resolving.de/urn:nbn:de:bvb:19-84072.
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Karlisch, Kaja [Verfasser], and Andreas [Gutachter] Friebe. "Die Rolle der PDE3 im cGMP/cAMP-Crosstalk in NO-GC-defizienten Mäusen / Kaja Karlisch. Gutachter: Andreas Friebe." Würzburg : Universität Würzburg, 2013. http://d-nb.info/1102826138/34.
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Kühn, Rainer. "Untersuchungen zur Bedeutung der cAMP- und cGMP- abhängigen Signaltransduktion in der Kontrolle der glatten Muskulatur des humanen Ureters : Eine funktionelle Studie." kostenfrei, 2008. http://edoc.ub.uni-muenchen.de/8407/.
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Dünnes, Sarah [Verfasser], Andreas [Gutachter] Friebe, and Erhard [Gutachter] Wischmeyer. "Einfluss der NO-sensitiven Guanylyl-Cyclase auf den cGMP/cAMP-Crosstalk und die Steifigkeit der murinen Aorta / Sarah Dünnes ; Gutachter: Andreas Friebe, Erhard Wischmeyer." Würzburg : Universität Würzburg, 2016. http://d-nb.info/1121508316/34.
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Marais, Erna. "Role of cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP) and p38 mitogen activated protein kinase (p38 MAPK) in preconditioning of the ischaemic myocardium." Thesis, Stellenbosch : Stellenbosch University, 2002. http://hdl.handle.net/10019.1/53039.
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Thesis (PhD)--University of Stellenbosch, 2002.<br>ENGLISH ABSTRACT: Ischaemic preconditioning (PC) is the phenomenon whereby a short episode of
coronary occlusion followed by reperfusion protects the myocardium against a
subsequent period of prolonged (also called index or sustained) ischaemia. Even
though the exact mechanism of PC remains to be established, it implies that the heart
has an endogenous protective mechanism against ischaemia which, if identified, may
have important clinical implications. The importance of establishing the mechanism of
PC lies in the potential to convert this biological phenomenon into a therapeutic modality
to be used clinically. If mediated by certain components of a signal transduction
pathway, such a goal will be achievable.
Several triggers and signal transduction pathways have been implicated in the mechanism
of protection induced by PC: for example, receptor-dependent endogenous triggers (such
as adenosine and opioids) and receptor-independent endogenous triggers (such as free
radicals and calcium). However, the involvement of both the ~-adrenergic signalling
pathway as well as nitric oxide (NO) in PC has not been defined.
It has been suggested that all triggers are linked to a common final pathway, for
example, activation of protein kinase C (PKC) and/or the mitogen-activated kinases
(MAPKs), in particular p38 MAPK. However, the role of the latter is still controversial.
The aim of this study was to:
(A) characterize changes in the cyclic nucleotides, cAMP and cGMP, and p38 MAPK
occurring during the entire experimental procedure in an attempt to gain insights into
the possible mechanisms involved in ischaemie PC (Chapter 3);
(8) establish the significance of the changes observed in cAMP and cGMP by
pharmacological manipulation of their respective pathways (Chapters 4 and 5);
(C) establish the role of p38 MAPK in ischaemie PC: trigger or mediator involvement
(Chapter 6).
Isolated perfused working rat hearts were preconditioned by 3 x 5 min global ischaemia,
interspersed by 5 min reperfusion, followed by 25 min global ischaemia and 30 min
reperfusion. Functional recovery during reperfusion was used as end-point. Hearts
were freeze-clamped at different times during the PC protocol, sustained ischaemia, as well as during reperfusion. Tissue cyclic nucleotides (cAMP and cGMP), cyclic
nucleotide phosphodiesterase (cAMP- and cGMP-PDE) activities, adenylyl cyclase and
protein kinase A activities and p-adrenergic receptor characteristics were determined.
p38 MAPK activation was also assessed by Western blotting, using dual phospho-p38
MAPK (Thr180ITyr182) antibody as well as activating transcription factor 2 (ATF2)
activation. In addition, to evaluate the role of p38 MAPK in PC protection, the effect of
inhibition of p38 MAPK activation, by 8B203580, was determined in adult isolated rat
cardiomyocytes as well as in isolated perfused rat hearts.
Based on the results obtained, it is proposed that during a multi-cycle ischaemie PC
protocol triggers (presumably endogenous catecholamines and NO) are released which
induce cyclic changes in cyclic nucleotides, cAMP and cGMP. Both these cyclic
nucleotides transiently activate the downstream stress kinase, p38 MAPK, which may
trigger further downstream adaptive processes.
Furthermore, the sustained ischaemic period of PC hearts was characterized by
attenuated cAMP and elevated cGMP levels, as well as attenuated activation of p38
MAPK, which was associated with cardioprotection. In addition, pharmacological
attenuation of p38 MAPK activation during sustained ischaemia led to functional recovery.
It is concluded that the cardioprotection of PC is due to attenuation of ischaemia-induced
p38 MAPK activation. Pharmacological manipulation of this kinase should be considered
as a therapeutic modality in the future.<br>AFRIKAANSE OPSOMMING: Isgemiese prekondisionering (PK) verwys na die verskynsel waardeur 'n kort,
verbygaande episode van isgemie gevolg deur herperfusie, die miokardium teen 'n
daaropvolgende langdurige periode van isgemie beskerm. Die presiese meganisme
van beskerming van PK moet nog opgeklaar word, maar dit impliseer dat die hart oor 'n
endogene beskermingsmeganisme beskik wat, indien geïdentifiseer, belangrike kliniese
implikasies mag hê. Die belang van opklaring van die meganisme van PK lê daarin dat
'n biologiese verskynsel in 'n terapeutiese modaliteit vir kliniese gebruik, omgeskakel
kan word. Sou dit deur bepaalde komponente van 'n seintransduksiepad gemedieër
word, is so 'n doel bereikbaar.
Verskeie stimuli en seintransduksiepaaie is in PK betrokke: byvoorbeeld, reseptorafhanklike
endogene stimuli (soos adenosien en opioïde), asook reseptor-onafhanklike
endogene stimuli (soos vrye radikale en kalsium). Die betrokkenheid van die padrenerge
seintransduksiepad asook stikstofoksied (NO) in PK egter nog nie behoorlik
evalueer nie.
Dit is voorgestel dat alle stimuli op 'n finale algemene pad uitloop, soos byvoorbeeld die
aktivering van protein kinase C (PKC) en/of die mitogeen-geaktiveerde kinases
(MAPKs), spesifiek die p38 MAPKs. Laasgenoemde se rol in PK is steeds
kontroversieël.
Die doel van die studie was dus:
(A) karakterisering van die veranderinge in die sikliese nukleotiede, cAMP en cGMP,
en p38 MAPK wat tydens die hele eksperimentele prosedure plaasvind, in 'n
poging om meer insig te verkry aangaande moontlike meganismes betrokke in
isgemiese PK (Hoofstuk 3);
(8) bepaling van die belang van die waargenome veranderinge in cAMP en cGMP
deur hulonderskeie paaie farmakologies te manipuleer (Hoofstukke 4 en 5);
(C) bepaling van die rol van p38 MAPK in PK: betrokkenheid as stimulus of mediator
(Hoofstuk 6).
Geïsoleerde, geperfuseerde werkende rotharte is geprekondisioneer deur blootstelling
aan 3 x 5 min globale isgemie, afgewissel met 5 min herperfusie, gevolg deur 25 min globale isgemie en 30 min herperfusie. Funksionele herstel tydens herperfusie is as
eindpunt gebruik. Harte is op verskillende tye tydens die PK protokol, volgehoue
isgemie, asook herperfusie gevriesklamp. Weefsel sikliese nukleotiede (cAMP en
cGMP), die aktiwiteit van sikliese nukleotied fosfodiesterases (cAMP- en cGMP-PDE),
adeniel siklase en protein kinase A (PKA) asook die eienskappe van die p-adrenerge
reseptor is gemeet. p38 MAPK aktivering is met Westerse oordragtegnieke bepaal,
deur van dubbel gefosforileerde p38 MAPK (Thr180fTyr182) antiliggame asook
geaktiveerde transkripsie faktor 2 (ATF2) gebruik te maak. Die rol van p38 MAPK in PK
beskerming is evalueer deur die effek van inhibisie van p38 MAPK aktivering met SB
203580, in volwasse geïsoleerde rot kardiomiosiete asook in geïsoleerde geperfuseerde
rotharte, te bepaal.
Na aanleiding van die resultate, is voorgestel dat, tydens 'n multi-siklus isgemie PK
protokol, stimuli (moontlik endogene katekolamiene en NO) vrygestel word wat die
sikliese veranderinge in sikliese nukleotiede, cAMP en cGMP, veroorsaak. Beide
hierdie sikliese nukleotiede aktiveer die distale stres kinase, p38 MAPK, op 'n
betekenisvolle, maar verbygaande manier. Hierdie kinase mag verdere distale
aanpassingsprosesse stimuleer.
Die volgehoue isgemiese periode van PK harte is gekenmerk deur verminderde cAMP
en verhoogde cGMP vlakke, asook verminderde aktivering van p38 MAPK. Hierdie
veranderinge is met beskerming van die hart teen isgemie geassosieer.
Daarbenewens, farmakologiese vermindering van p38 MAPK aktivering tydens
volgehoue isgemie het tot verbeterde funksionele herstel gelei. Die gevolgtrekking is
gemaak dat die beskermende effek van PK die gevolg is van verminderde aktivering
van isgemies-geïnduseerde p38 MAPK. Farmakologiese manipulasie van hierdie
kinase moet in die toekoms as terapeutiese modaliteit oorweeg word.
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Dünnes, Sarah Verfasser], Andreas [Gutachter] [Friebe, and Erhard [Gutachter] Wischmeyer. "Einfluss der NO-sensitiven Guanylyl-Cyclase auf den cGMP/cAMP-Crosstalk und die Steifigkeit der murinen Aorta / Sarah Dünnes ; Gutachter: Andreas Friebe, Erhard Wischmeyer." Würzburg : Universität Würzburg, 2016. http://d-nb.info/1121508316/34.
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MARTINS, Daniella Ramos. "Avaliação do relaxamento vascular induzido por um novo derivado pirazólico protótipo a fármaco (LQFM 021), possível inibidor de fosfodiesterase." Universidade Federal de Goiás, 2012. http://repositorio.bc.ufg.br/tede/handle/tde/2110.
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Previous issue date: 2012-02-28<br>The inhibition of phosphodiesterases (PDEs) increases intracellular levels of cyclic nucleotides 3 ': 5'-cyclic adenosine monophosphate (cAMP) and 3 ': 5'-cyclic guanosine monophosphate (cGMP), which has many physiological and biochemical effects, especially in cardiovascular system. The objective of this study was to analyze the pharmacological effects of a new compound derived from pyrazole, LQFM 021, which was indicated by molecular modeling studies as a possible inhibitor of PDE-3. For this purpose, aortas were isolated of rats and mounted in organ baths for isometric tension recording of the relaxing effect of LQFM 021, in preparations pre-contracted with phenylephrine. We analyzed the involvement of the vascular endothelium, soluble guanylate cyclase (sGC) and adenylate cyclase (AC), the role of K+ channels and Ca2+, besides the contribution of Ca2+ uptake by the sarcoplasmic reticulum. As a result, was demonstrated that the LQFM 021 induces vascular relaxation (Emax: 54.9 ± 6.0%), being this relaxation potentiated by endothelium (Emax: 88.1 ± 2.1%). The inhibition of AC with MDL-12.330A (10 μM) or of the sGC with ODQ (1 μM) reduced the relaxation of 88.1 ± 2.1%, to 48.35 ± 3.01% and 19.95 ± 2.32%, respectively. The pre-contraction with KCl 45 mM or treatment of preparations with TEA (5 mM), reduced almost completely the relaxing effect of the compound. Inhibition of Ca2+ / ATPase reticular with CPA (10 mM) reduced the relaxation stimulated by 021 LQFM approximately 66.5%. Concentration-response curve contractile induced by phenylephrine (0.1 nM to 1 μM) or by CaCl2 (0-3 mM, zero-calcium + phenylephrine) were reduced by pretreatment of preparations with LQFM 021 (EC50). In conclusion, this study showed that the new synthetic derivative of pyrazole LQFM 021 is a potential inhibitor of PDE-3 and has vasorelaxant activity. The endothelium potentiates the relaxation stimulated by the compound. The route of sGC and AC are involved in the mechanism of action of LQFM 021. Was also evidenced by participation from sarcoplasmatic reticulum, well as the flow of K+ and Ca2+ through the cell membrane.<br>A inibição das fosfodiesterases (PDEs) aumenta os níveis intracelulares de nucleotídeos cíclicos 3' : 5'-monofosfato cíclico de adenosina (AMPc) e 3' : 5'-monofosfato cíclico de guanosina (GMPc), os quais tem muitos efeitos fisiológicos e bioquímicos, sobretudo no sistema cardiovascular. O objetivo deste estudo foi analisar os efeitos farmacológicos de um novo composto derivado do pirazol, LQFM 021, o qual foi apontado por estudos de modelagem molecular como possível inibidor de PDE-3. Para tanto, artérias aortas de ratos foram isoladas e montadas em banhos de órgão para registro da tensão isométrica do efeito relaxante do LQFM 021, em preparações pré-contraídas com fenilefrina. Foi analisada a participação do endotélio vascular, da guanilato ciclase solúvel (GCs) e da adenilato ciclase (AC), o papel dos canais de K+ e de Ca2+, além da contribuição da captação de Ca2+ pelo retículo sarcoplasmático. Como resultado, foi demonstrado que o LQFM 021 induz relaxamento vascular (Emax: 54.9 ± 6.0%), sendo este relaxamento potencializado pelo endotélio (Emax:88.1 ± 2.1%). A inibição da AC com MDL-12.330A (10 μM) ou da GCs com ODQ (1 μM), reduziram o relaxamento de 88,1 ± 2,1%, para 48,35 ± 3,01% e 19,95 ± 2,32%, respectivamente. A pré-contração com KCl 45 mM ou o tratamento das preparações com TEA (5 mM), reduziram quase que por completo o efeito relaxante do composto. A inibição da Ca2+/ATPase reticular com CPA (10 μM), reduziu o relaxamento estimulado pelo LQFM 021 em aproximadamente 66,5%. Curva concentração-resposta contrátil induzida pela fenilefrina (0,1 nM a 1 μM) ou pelo CaCl2 (0 a 3 mM, em meio zero-cálcio + fenilefrina) foram reduzidas pelo pré-tratamento das preparações com LQFM 021 (EC50). Em conclusão, este estudo mostrou que o novo derivado sintético de pirazol LQFM 021 é um possível inibidor de PDE-3 e possui atividade vasorelaxante. O endotélio participa e potencializa o relaxamento estimulado pelo composto. A via da GCs e AC estão envolvidas no mecanismo de ação do LQFM 021. Também foi evidenciada a participação do retículo sarcoplasmático, bem como o fluxo de K+ e de Ca2+ através da membrana celular.
Books on the topic "CAMP/cGMP"
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Schmidt, Ulrike. Secondary Messenger Systems in PTSD. Edited by Israel Liberzon and Kerry J. Ressler. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780190215422.003.0014.
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Second messengers such as cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), inositoltriphosphate, and diacylglycerol (DAG) are a prerequisite for the signal transduction of extracellular receptors. The latter are central for cellular function and thus are implicated in the pathobiology of a variety of disorders, such as schizophrenia, bipolar disorder, major depression, and post-traumatic stress disorder (PTSD). This chapter focuses on the involvement of second messenger molecules and their regulators as direct targets in human and animal PTSD and aims to stimulate the underdeveloped research in this field. The synthesis of literature reveals that second messengers clearly play a central role in PTSD-associated brain regions and processes. In particular, pituitary adenylate cyclase-activating polypeptide (PACAP), an important regulator of intracellular cAMP levels, as well as protein kinase c, the major target of DAG, belong to the hitherto most promising PTSD candidate molecules directly involved in second messenger signaling.
Book chapters on the topic "CAMP/cGMP"
1
Corbin, Jackie D., Stephen J. Beebe, Charles E. Cobb, et al. "Signal Transduction through cAMP and cGMP." In Signal Transduction and Protein Phosphorylation. Springer US, 1987. http://dx.doi.org/10.1007/978-1-4757-0166-1_2.
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Reverte-Salisa, Laia, Abhishek Sanyal, and Alexander Pfeifer. "Role of cAMP and cGMP Signaling in Brown Fat." In Brown Adipose Tissue. Springer International Publishing, 2018. http://dx.doi.org/10.1007/164_2018_117.
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Gjuric, M., N. Thürauf, and H. Hatt. "Charakterisierung und Differenzierung cAMP/cGMP-abhängiger Ionenkanäle olfaktorischer Sinnes- und Stützzellen." In Sitzungsbericht. Springer Berlin Heidelberg, 1994. http://dx.doi.org/10.1007/978-3-642-85188-9_58.
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Rascon, A., P. Belfrage, E. Degerman, et al. "Purification of a cGMP-inhibited cAMP Phosphodiesterase from Vascular Smooth Muscle." In Purines in Cellular Signaling. Springer New York, 1990. http://dx.doi.org/10.1007/978-1-4612-3400-5_51.
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Taban, C. H., and M. Cathieni. "Second Messengers in Newt Limb Regeneration: cAMP and cGMP Levels and Distribution." In Recent Trends in Regeneration Research. Springer US, 1989. http://dx.doi.org/10.1007/978-1-4684-9057-2_9.
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Lorenz, Robin, Daniela Bertinetti, and Friedrich W. Herberg. "cAMP-Dependent Protein Kinase and cGMP-Dependent Protein Kinase as Cyclic Nucleotide Effectors." In Non-canonical Cyclic Nucleotides. Springer International Publishing, 2015. http://dx.doi.org/10.1007/164_2015_36.
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Sassi, Yassine, and Jean-Sébastien Hulot. "Pulmonary Hypertension: Novel Pathways and Emerging Therapies Inhibitors of cGMP and cAMP Metabolism." In Handbook of Experimental Pharmacology. Springer Berlin Heidelberg, 2013. http://dx.doi.org/10.1007/978-3-662-45805-1_20.
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Paul, N. E., K. Hemmrich, C. Gummersbach, C. V. Suschek, K. Kröncke, and N. Pallua. "The impact of cGMP and cAMP dependent pathways on the differentiation of human preadipocytes." In Deutsche Gesellschaft für Chirurgie. Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-642-00625-8_96.
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Whalin, M. W., S. J. Strada, J. G. Scammell, and W. J. Thompson. "Regulation of cAMP Metabolism in PC12 Cells by Type II (cGMP-Activatable) Cyclic Nucleotide Phosphodiesterase." In Purines in Cellular Signaling. Springer New York, 1990. http://dx.doi.org/10.1007/978-1-4612-3400-5_47.
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Tegge, W., W. Dostmann, F. Hofmann, and R. Frank. "Determination of the specificities of cAMP— and cGMP— dependent protein kinases with peptide libraries on cellulose paper." In Peptides 1994. Springer Netherlands, 1995. http://dx.doi.org/10.1007/978-94-011-1468-4_217.
Full textConference papers on the topic "CAMP/cGMP"
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Maurice, D. H., and R. J. Haslam. "ROLES OF cAMP AND cGMP IN THE SYNERGISTIC INHIBITORY EFFECTS OF NITROVASODILATORS AND PGE1 ON PLATELET AGGREGATION AND DEGRANULATION." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644533.
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Washed rabbit platelets labelled with [14C]5-HT and suspended in a modified Tyrode’s solution were used in this study. Incubation of the platelets with 0.1, 1 and 10 μM sodium nitro-prusside (SNP) for 30 s inhibited aggregation induced by 10 nM platelet-activating factor by 7, 13 and 45% and the release of [14C]5-HT by 16, 30 and 45%, respectively. In combination with 0.02 μM PGE1, which had little effect alone (7% inhibitions), these concentrations of SNP caused 58, 90 and 100% inhibitions of aggregation and 60, 73 and 81% inhibitions of [14C]5-HT release. Thus, SNP and PGE1 acted synergisti-cally. The changes in [3H]cGMP and [3H]cAMP caused by these compounds were measured in platelets labelled by preincubation with [3H]guanine and [3H]adenine. [3H]cGMP (initially 0.01% of platelet [3H]GTP) increased by amounts equivalent to 0.02, 0.10 and 0.63% of [3H]GTP with 0.1, 1 and 10 μM SNP. PGE1 had no effects on platelet [3H]cGMP. The above SNP concentrations also increased [3H]cAMP by amounts equivalent to 0.01, 0.02 and 0.04% of platelet [3H]ATP (basal value 0.02%). However, in the presence of 0.02 μM PGE1, 0.1, 1 and 10 μM SNP increased [3H]cAMP by amounts equivalent to 0.13, 0.26 and 0.39% of platelet [3H]ATP. Both with and without PGE1, 10 μM SIN-1 (the active metabolite of molsidomine) had effects similar to those of 1 μM SNP. Thus, the synergistic actions of PGE-, and SNP or SIN-1 on platelet function correlated with increases in [3H]cAMP, not [3H]cGMP. Preincubation of the platelets for 30 s with 200 μM 2∲,5∲-dideoxy-adenosine (an inhibitor of adenylate cyclase) reduced the above increases in [3H]cAMP and inhibitions of platelet reactions by about 60%, without affecting [3H]cGMP levels. Addition of specific inhibitors of platelet cAMP phosphodiesterase (e.g. cilostamide) enhanced the actions of PGE1 in a manner similar to SNP but had little effect on the actions of SNP. The results show that the nitrovasodilators studied have effects on platelet function and [3H]cAMP similar to those of inhibitors of cAMP phosphodiesterase, suggesting that their actions may be mediated by increases in cAMP caused by an effect of cGMP on the platelet cGMP-inhibited cAMP phosphodiesterase. (HSFO Grant T443H)
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Grant, P. G., A. F. Mannarino, and R. W. Colman. "REGULATION OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASE ACTIVITY IN PLATELETS BY PHOSPHORYLATION." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1642820.
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Cyclic nucleotide phosphodiesterases (PDE) provide the only known pathway for the hydrolysis of cyclic nucleotides in cells and thus have the potential for modulating the effects of cAMP and cGMP on cells. In platelets a rise in intracellular cAMP levels inhibits platelet aggregation and secretion. Since cAMP exerts many of its effects through a cAMP-dependent kinase we questioned whether phosphorylation of cAMP PDE might be a mode for regulation of PDE activity in platelets. When platelets were incubated for 10 min with forskolin (100 μM) the level of cAMP rose at least 10-fold.When the low Km cyclic nucleotide PDE was isolated from freeze-thaw lysates of forskolin treated platelets by chromatography on blue dextran-Sepharose, the specific activity of this enzyme was increased 3 to 13-fold over similarly processed control platelets. The specific activity of a second PDE, the cGMP-stimulated cAMP PDE, was increased 1.5 to 3-fold by forskolin treatment of platelets. Forskolin had no direct effect on either purified PDE. The stimulation of the low Km cAMP PDE activity by exposure of platelets to forskolin was blocked when the platelets were simultaneously treated with the protein kinase inhibitor H-8 (100 μM) which is most potent toward cAMP dependent protein kinase indicating that this kinase may be responsible for the stimulation. When platelets which had been prelabeled with 32P inorganic phosphate were treated with forskolin and the low Km cAMP PDE isolated by blue dextran-Sepharose chromatography, a protein migrating in SDS gels at Mr=110,000, the molecular weight of the low Km cAMP PDE, was labeled indicating that phosphorylation of the PDE occurred coincident with stimulation of activity. These results suggest that phosphorylation of the low Km cAMP PDE by protein kinase may be an important regulatory mechanism for cAMP PDE activity and cyclic nucleotide levels in platelets.
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Khatib, SY, and A. Badwan. "Bronchodilation Effects of PDE5 Inhibitors (Sildenafil & Ordonofil): Role of cGMP/cAMP-NO." In American Thoracic Society 2009 International Conference, May 15-20, 2009 • San Diego, California. American Thoracic Society, 2009. http://dx.doi.org/10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a2437.
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Ochoa, Cristhiaan, Mikhail Alexeyev, Dara Frank, and Troy Stevens. "Pseudomonas Aeruginosa Exotoxin Y Increases Intracellular Levels Of Both CAMP And CGMP In Pulmonary Microvascular Endothelial Cells." In American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado. American Thoracic Society, 2011. http://dx.doi.org/10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a4179.
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Drndarski, Svetlana, Greg A. Knock, Philip I. Aaronson, and Jeremy P. T. Ward. "Diverging Effects Of The Cyclic Nucleotide Antagonists Rp-8Br-cGMP And Rp-8Br-cAMP In Rat Pulmonary And Mesenteric Artery." In American Thoracic Society 2010 International Conference, May 14-19, 2010 • New Orleans. American Thoracic Society, 2010. http://dx.doi.org/10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a6279.
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Asaji, T., E. Murakami, N. Takekoshi, S. Matsui, and T. Imaoka. "EFFECT OF ATRIAL NATRIURETIC POLYPEPTIDES ON PLATELET FUNCTION." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644872.
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Atrial natriuretic polypeptides (ANP) have been shown to possess a potent diuretic and natriuretic activity, and medicated to patients with heart insufficiency as a drug to be mediated by cGMPaccumulation in glomeruli. A existence of receptors for ANP have recently beenreported in human platelet. But, whether ANP has a direct effect on platelet function remains to be known.Single stimulation of ANP in any concentration did not induce aggregation in neither platelet rich plasma, nor washed platelets. Also no effect of pretreatment with ANP was observed against aggregation triggered by known mediators of platelet activation (Thrombin, ADP, Epinephrine, Collagen) using platelet rich plasma and washed platelets.Therefore, biochemical parameters such as cyclic nucleotides (cAMP, cGMP), phosphatidylinositol hydrolysis and protein phosphorylation, leading to the early stage of platelet activation were examined to investigate the effect of ANP in receptor linked transducing mechanism. Neither cyclic nucleotides accumulation nor [32 P] phosphatidic acid production were detected in platelets treated with ANP. ANP caused a small increase of 32P incorporation into M 30K protein, but no change on the level of phosphorylation of 47K, 20K protein (Imaoka, T. and Haslam, R.J., J.Biol.Chem.258,11404, 1983) was observed.These results clearly suggested thatANP binding with membrane receptor was not linked with adenylate cyclase, ganulate cyclase and phosphatidylinositol phosphate turnover in human platelet, maybe because of too few numbers of ANP receptor. Mechanism of 30K protein phosphorylation and Ca++ mobilization are important subjects for future study, (supported by MESC of Japan)
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Moffat, Katrina J., and D. Euan MacIntyre. "REGULATION OF RECEPTOR-OPERATED Ca2− CHANNEL OPENING IN HUMAN PLATELETS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644677.
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Agonist-induced elevation of the platelet intracellular free Ca2+ concentration ([Ca2−]i), as monitored using quin2, is not electrically mediated and is attenuated by removal of extracellular Ca2− and by lanthanides (e.g Gd3−).Collectively these data suggest that elevation of [Ca2−]i in platelets derives in part via influx of external Ca2−presumably through a receptor-operated Ca2− channel (ROC). Hal lam & Rink (FEBS Lett. 186: 175: 1985) showed that Mn2−also enters platelets via these ROC. To investigate the possible regulatory mechanisms that govern ROC status, we utilized quin2-labelled human platelets suspended in a Ca2+-free Hepes buffered Tyrodes solution, and monitored agonist-induced Mn2+-mediated quenching of quin2 fluorescence as an index of ROC opening.Thrombin (Th, 0.01-1 U/ml), Vasopressin (VP, 10-1000 nM) and the TxA2-mitnetic, EP171 (1-100 nM) all induced ROC opening which occurred rapidly (<30s), was maximal within 30-60s and thereafter declined. Gd3+ (≤2 mM) markedly impaired this Mn2ࢤ-mediated quenching of quin2 fluorescence induced by all 3 agonists. The adenylate cyclase stimulant PGD2 (3-3000 nM) and the guanylate cyclase stimulant sodium nitroprusside (0.01-10 μM) impaired ROC opening induced by Th (0.5 U/ml), VP (100 nM) and EP171 (25 nM) whether added to platelets ≤120sbefore or 30s after the agonists. In contrast, agents that selectively antagonize, at the receptor level, the effects of VP (e.g. d(CH2)5Tyr Me AVP, 10 ¼H) or EP171 (e.g.EP092, 250nM), or that inhibit the action of Th(e.g. Hirudin 1 U/ml)only impaired ROC opening when added to platelets simultaneously with or before the agonist.These results indicate that, although initiated by agonist-receptor interaction, maintenance of the open state of ROC in human platelets does not require continued receptor occupancy or activation by agonist. Moreover, besides acting to impair the transduction processes initiated following occupancy by agonist of platelet Vi, TP and Thrombin receptors, cAMP-and cGMP-dependent reactions also can terminate or otherwise limit opening of ROC.