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1
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 (December 1, 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 (November 1, 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 (December 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, A. Tamura, Y. Tsukahara, Y. Nakaoka, E. Iwai, and T. Sato. "Simple fluctuation of Ca2+ elicits the complex circadian dynamics of cyclic AMP and cyclic GMP in Paramecium." Journal of Cell Science 112, no. 2 (January 15, 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 (January 19, 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 (April 15, 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 (August 15, 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 (July 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 (May 1, 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 (March 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.
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Frajnt, Magdalena, Małgorzata Cytryńska, and Teresa Jakubowicz. "The effect of cAMP and cGMP on the activity and substrate specificity of protein kinase A from methylotrophic yeast Pichia pastoris." Acta Biochimica Polonica 50, no. 4 (December 31, 2003): 1111–18. http://dx.doi.org/10.18388/abp.2003_3635.
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Cyclic AMP dependent protein kinase (PKA) from Pichia pastoris yeast cells was found to be activated by either cAMP or cGMP. Analogs of cAMP such as 8-chloro-cAMP and 8-bromo-cAMP were as potent as cAMP in PKA activation while N6,2'-O-dibutyryl-cAMP did not stimulate the enzyme activity. It was shown that protamine sulfate was almost equally phosphorylated in the presence of 1-2 x 10(-6)M cAMP or cGMP while other substrates such as Kemptide, ribosomal protein S6, were phosphorylated to a lower extent in the presence of cGMP. It was demonstrated that pyruvate kinase is a substrate of PKA which co-purified with the P.pastoris enzyme. Moreover, pyruvate kinase was phosphorylated by PKA in the presence of cAMP and cGMP to comparable levels.
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Golin-Bisello, Franca, Neil Bradbury, and Nadia Ameen. "STa and cGMP stimulate CFTR translocation to the surface of villus enterocytes in rat jejunum and is regulated by protein kinase G." American Journal of Physiology-Cell Physiology 289, no. 3 (September 2005): C708—C716. http://dx.doi.org/10.1152/ajpcell.00544.2004.
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The cystic fibrosis transmembrane conductance regulator (CFTR) is critical to cAMP- and cGMP-activated intestinal anion secretion and the pathogenesis of secretory diarrhea. Enterotoxins released by Vibrio cholerae (cholera toxin) and Escherichia coli (heat stable enterotoxin, or STa) activate intracellular cAMP and cGMP and signal CFTR on the apical plasma membrane of small intestinal enterocytes to elicit chloride and fluid secretion. cAMP activates PKA, whereas cGMP signals a cGMP-dependent protein kinase (cGKII) to phosphorylate CFTR in the intestine. In the jejunum, cAMP also regulates CFTR and fluid secretion by insertion of CFTR from subapical vesicles to the surface of enterocytes. It is unknown whether cGMP signaling or phosphorylation regulates the insertion of CFTR associated vesicles from the cytoplasm to the surface of enterocytes. We used STa, cell-permeant cGMP, and cAMP agonists in conjunction with PKG and PKA inhibitors, respectively, in rat jejunum to examine whether 1) cGMP and cGK II regulate the translocation of CFTR to the apical membrane and its relevance to fluid secretion, and 2) PKA regulates cAMP-dependent translocation of CFTR because this intestinal segment is a primary target for toxigenic diarrhea. STa and cGMP induced a greater than fourfold increase in surface CFTR in enterocytes in association with fluid secretion that was inhibited by PKG inhibitors. cAMP agonists induced a translocation of CFTR to the cell surface of enterocytes that was prevented by PKA inhibitors. We conclude that cAMP and cGMP-dependent phosphorylation regulates fluid secretion and CFTR trafficking to the surface of enterocytes in rat jejunum.
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Cytrynska, Malgorzata, Iwona Wojda, Magdalena Frajnt, and Teresa Jakubowicz. "PKA from Saccharomyces cerevisiae can be activated by cyclic AMP and cyclic GMP." Canadian Journal of Microbiology 45, no. 1 (January 1, 1999): 31–37. http://dx.doi.org/10.1139/w98-214.
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Analysis of Saccharomyces cerevisiae genome revealed no sequence homologous to cyclic GMP (cGMP) dependent protein kinase from other organisms. Here we demonstrate that cyclic AMP (cAMP) dependent protein kinase purified from S. cerevisiae was almost equally activated by cAMP and cGMP at 3 × 10-6 M concentrations of either nucleotide in the presence of Mg2+ ions. Interestingly, if Mn2+ ions were used instead of Mg2+, cGMP was only 30% as effective as cAMP in the activation of cAMP-dependent protein kinase. Analogs of cAMP such as 8-chloro-cAMP and 3':5'-cyclic monophosphate of ribofuranosylbenzimidazole were as potent as cAMP in the enzyme activation, while N6,2'-O-dibutyryl-cAMP activated the enzyme to a lower extent. It was also found that yeast cAMP-dependent protein kinase can be activated by limited proteolytic digestion. The results presented were obtained with protamine and ribosomal protein S10 used as phosphorylation substrates.Key words: cAMP-dependent protein kinase, cAMP, cGMP, yeast, ribosomal protein S10.
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Sheth, S. B., and R. W. Colman. "Platelet cAMP and cGMP Phosphodiesterases." Platelets 6, no. 2 (January 1995): 61–70. http://dx.doi.org/10.3109/09537109509078445.
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Henkin, R. I., and I. Velicu. "cAMP and cGMP in nasal mucus: relationships to taste and smell dysfunction, gender and age." Clinical & Investigative Medicine 31, no. 2 (April 1, 2008): 71. http://dx.doi.org/10.25011/cim.v31i2.3366.
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Purpose: To evaluate the presence and concentration of cAMP and cGMP in human nasal mucus in normal volunteers, to relate these findings to age and gender, and to compare normal levels with those in patients with taste and smell dysfunction. Methods: Nasal mucus was collected over one to four days in 66 normal subjects and 203 patients with smell loss (hyposmia). Samples were centrifuged at 20,000 rpm, the supernatant removed and analyzed for cAMP and cGMP by using a 96 plate technique with a specific spectrophotometric colorimetric ELISA assay. Results: Both cAMP and cGMP were present in human nasal mucus with both cAMP and cGMP significantly higher in normal women than in normal men [men vs. women; cAMP, 0.23±0.002 vs. 0.34±0.05 (P < 0.05); cGMP, 0.28±0.03 vs. 0.63±0.12 (P < 0.01)]. Both cAMP and cGMP changed with age; both moieties increased in a U shaped, parabolic pattern reaching a peak at age 41-50 with cAMP diminishing thereafter and then increasing to its highest level over age 70. Both cAMP and cGMP were lower in patients with taste and smell dysfunction than in normal subjects [normals vs. patients; cAMP, 0.31±0.05 vs. 0.15±0.02 (P < 0.01); cGMP, 0.56±0.07 vs. 0.025±0.02 (P < 0.001)] suggesting a relationship to olfactory pathology. Conclusions: This is the first definitive study to demonstrate the presence of these cyclic nucleotides in nasal mucus and the first to reveal decreased levels in patients with impaired taste and smell function. Since olfactory receptor sensitivity decreases with age increased nasal mucus cAMP over age 70 may appear incongruous but suggests one role of cAMP in olfactory function may relate to feedback mechanism(s) whereby its increase over age 70 yr reflects a physiological attempt to enhance diminishing lfactory function through growth and development of olfactory receptor activity.
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Bosgraaf, Leonard, Henk Russcher, Helena Snippe, Sonya Bader, Joyce Wind, and Peter J. M. Van Haastert. "Identification and Characterization of Two Unusual cGMP-stimulated Phoshodiesterases in Dictyostelium." Molecular Biology of the Cell 13, no. 11 (November 2002): 3878–89. http://dx.doi.org/10.1091/mbc.e02-05-0302.
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Recently, we recognized two genes, gbpA andgbpB, encoding putative cGMP-binding proteins with a Zn2+-hydrolase domain and two cyclic nucleotide binding domains. The Zn2+-hydrolase domains belong to the superfamily of β-lactamases, also harboring a small family of class II phosphodiesterases from bacteria and lower eukaryotes. Gene inactivation and overexpression studies demonstrate thatgbpA encodes the cGMP-stimulated cGMP-phosphodiesterase that was characterized biochemically previously and was shown to be involved in chemotaxis. cAMP neither activates nor is a substrate of GbpA. The gbpB gene is expressed mainly in the multicellular stage and seems to encode a dual specificity phosphodiesterase with preference for cAMP. The enzyme hydrolyses cAMP ∼9-fold faster than cGMP and is activated by cAMP and cGMP with aK A value of ∼0.7 and 2.3 μM, respectively. Cells with a deletion of the gbpB gene have increased basal and receptor stimulated cAMP levels and are sporogeneous. We propose that GbpA and GbpB hydrolyze the substrate in the Zn2+-hydrolase domain, whereas the cyclic nucleotide binding domains mediate activation. The human cGMP-stimulated cAMP/cGMP phosphodiesterase has similar biochemical properties, but a completely different topology: hydrolysis takes place by a class I catalytic domain and GAF domains mediate cGMP activation.
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Weiss, Harvey R., Gary X. Gong, Michaela Straznicka, Lin Yan, James Tse, and Peter M. Scholz. "Cyclic GMP and cyclic AMP induced changes in control and hypertrophic cardiac myocyte function interact through cyclic GMP affected cyclic-AMP phosphodiesterases." Canadian Journal of Physiology and Pharmacology 77, no. 6 (July 1, 1999): 422–31. http://dx.doi.org/10.1139/y99-039.
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We tested the hypothesis that the negative functional effects of cyclic GMP (cGMP) would be greater after increasing cyclic AMP (cAMP), because of the action of cGMP-affected cAMP phosphodiesterases in cardiac myocytes and that this effect would be altered in left ventricular hypertrophy (LVH) produced by aortic valve plication. Myocyte shortening data were collected using a video edge detector, and O2 consumption was measured by O2 electrodes during stimulation (5 ms, 1 Hz, in 2 mM Ca2+) from control (n = 7) and LVH (n = 7) dog ventricular myocytes. cAMP and cGMP were determined by a competitive binding assay. cAMP was increased by forskolin and milrinone (10-6 M). cGMP was increased with zaprinast and decreased by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxilin-1-one (ODQ) both at 10-6 and 10-4 M, with and without forskolin or forskolin + milrinone. Zaprinast significantly decreased percent shortening in control (9 ± 1 to 7 ± 1%) and LVH (10 ± 1 to 7 ± 1%) myocytes. It increased cGMP in control (36 ± 5 to 52 ± 7 fmol/105 myocytes) and from the significantly higher baseline value in LVH (71 ± 12 to 104 ± 18 fmol/105 myocytes). ODQ increased myocyte function and decreased cGMP levels in control and LVH myocytes. Forskolin + milrinone increased cAMP levels in control (6 ± 1 to 15 ± 2 pmol/105 myocytes) and LVH (8 ± 1 to 18 ± 2 pmol/105 myocytes) myocytes, as did forskolin alone. They also significantly increased percent shortening. There were significant negative functional effects of zaprinast after forskolin + milrinone in control (15 ± 2 to 9 ± 1%), which were greater than zaprinast alone, and LVH (12 ± 1 to 9 ± 1%). This was associated with an increase in cGMP and a reduction in the increased cAMP induced by forskolin or milrinone. ODQ did not further increase function after forskolin or milrinone in control myocytes, despite lowering cGMP. However, it prevented the forskolin and milrinone induced increase in cAMP. In hypertrophy, ODQ lowered cGMP and increased function after forskolin. ODQ did not affect cAMP after forskolin and milrinone in LVH. Thus, the level of cGMP was inversely correlated with myocyte function. When cAMP levels were elevated, cGMP was still inversely correlated with myocyte function. This was, in part, related to alterations in cAMP. The interaction between cGMP and cAMP was altered in LVH myocytes.Key words: second messengers, cyclic AMP, cyclic GMP, cardiac myocyte function, cyclic GMP dependent cyclic-AMP phosphodiesterases, left ventricular hypertrophy, dog.
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Jackson, Edwin K., Zaichuan Mi, Keri Janesko-Feldman, Travis C. Jackson, and Patrick M. Kochanek. "2′,3′-cGMP exists in vivo and comprises a 2′,3′-cGMP-guanosine pathway." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 316, no. 6 (June 1, 2019): R783—R790. http://dx.doi.org/10.1152/ajpregu.00401.2018.
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The discovery in 2009 that 2′,3′-cAMP exists in biological systems was rapidly followed by identification of 2′,3′-cGMP in cell and tissue extracts. To determine whether 2′,3′-cGMP exists in mammals under physiological conditions, we used ultraperformance LC-MS/MS to measure 2′,3′-cAMP and 2′,3′-cGMP in timed urine collections (via direct bladder cannulation) from 25 anesthetized mice. Urinary excretion rates (means ± SE) of 2′,3′-cAMP (15.5 ± 1.8 ng/30 min) and 2′,3′-cGMP (17.9 ± 1.9 ng/30 min) were similar. Mice also excreted 2′-AMP (3.6 ± 1.1 ng/20 min) and 3′-AMP (9.5 ± 1.2 ng/min), hydrolysis products of 2′,3′-cAMP, and 2′-GMP (4.7 ± 1.7 ng/30 min) and 3′-GMP (12.5 ± 1.8 ng/30 min), hydrolysis products of 2′,3′-cGMP. To validate that the chromatographic signals were from these endogenous noncanonical nucleotides, we repeated these experiments in mice ( n = 18) lacking 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase), an enzyme known to convert 2′,3′-cyclic nucleotides to their corresponding 2′-nucleotides. In CNPase-knockout mice, urinary excretions of 2′,3′-cAMP, 3′-AMP, 2′,3′-cGMP, and 3′-GMP were increased, while urinary excretions of 2′-AMP and 2′-GMP were decreased. Infusions of exogenous 2′,3′-cAMP increased urinary excretion of 2′,3′-cAMP, 2′-AMP, 3′-AMP, and adenosine, whereas infusions of exogenous 2′,3′-cGMP increased excretion of 2′,3′-cGMP, 2′-GMP, 3′-GMP, and guanosine. Together, these data suggest the endogenous existence of not only a 2′,3′-cAMP-adenosine pathway (2′,3′-cAMP → 2′-AMP/3′-AMP → adenosine), which was previously identified, but also a 2′,3′-cGMP-guanosine pathway (2′,3′-cGMP → 2′-GMP/3′-GMP → guanosine), observed here for the first time. Because it is well known that adenosine and guanosine protect tissues from injury, our data support the concept that both pathways may work together to protect tissues from injury.
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Bkaily, G., and N. Sperelakis. "Injection of guanosine 5'-cyclic monophosphate into heart cells blocks calcium slow channels." American Journal of Physiology-Heart and Circulatory Physiology 248, no. 5 (May 1, 1985): H745—H749. http://dx.doi.org/10.1152/ajpheart.1985.248.5.h745.
Full textAbstract:
The role of guanosine 5'-cyclic monophosphate (cGMP) in the regulation of the ionic slow channels in heart muscle is less well known than that of adenosine 3,'5'-cyclic monophosphate (cAMP). The effects of intracellular injection of cAMP and cGMP in cultured chick embryonic heart (ventricular) cells by the liposome method were studied. Injection of cAMP into the cells induced spontaneous slow action potentials that could be blocked by verapamil and nifedipine. Injection of cGMP blocked on-going slow action potentials, and this effect was reversed by increasing cAMP. Thus both cAMP and cGMP are involved in the regulation of the slow calcium channels in myocardial cells, and the two cyclic nucleotides are antagonistic.
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MacKENZIE, Christopher J., Jill M. WAKEFIELD, Fiona CAIRNS, Anna F. DOMINICZAK, and Gwyn W. GOULD. "Regulation of glucose transport in aortic smooth muscle cells by cAMP and cGMP." Biochemical Journal 353, no. 3 (January 25, 2001): 513–19. http://dx.doi.org/10.1042/bj3530513.
Full textAbstract:
We have studied the ability of cGMP and cAMP to modulate platelet-derived growth factor (PDGF)-stimulated 2-deoxy-d-glucose (deGlc) transport in primary cultures of vascular smooth muscle cells (VMSC) from rat aorta. PDGF stimulated deGlc transport in a time- and concentration-dependent manner. 8-Bromo-cGMP and atrial natriuretic peptide(1–28) [ANP(1–28)] were found to reduce PDGF-stimulated deGlc transport without affecting basal (unstimulated) transport activity. In contrast, 8-bromo-cAMP and dibutyryl-cAMP stimulated basal deGlc transport 2-fold and were without effect on PDGF-stimulated deGlc transport. 8-Bromo-cGMP also inhibited 8-bromo-cAMP-stimulated deGlc transport. The stimulation of deGlc transport by PDGF was sensitive to the mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) kinase (MEK) inhibitor PD98059, and we show that ERK1/2 was activated by PDGF. Neither 8-bromo-cGMP nor ANP(1–28) inhibited PDGF-stimulated ERK activation, suggesting that the effects of cGMP and ANP(1–28) were not mediated by inhibition of this kinase. Our data also argue against a role for cGMP-dependent protein kinase in mediating the effects of cGMP or ANP(1–28). Collectively, our data suggest that in VSMC: (i) cGMP and cAMP have opposing effects on deGlc transport; (ii) PDGF and cAMP have common elements in the pathways by which they activate deGlc transport; and (iii) a common element may be the target of the cGMP-mediated inhibition of deGlc transport.
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Assender, J. W., K. M. Southgate, M. B. Hallett, and A. C. Newby. "Inhibition of proliferation, but not of Ca2+ mobilization, by cyclic AMP and GMP in rabbit aortic smooth-muscle cells." Biochemical Journal 288, no. 2 (December 1, 1992): 527–32. http://dx.doi.org/10.1042/bj2880527.
Full textAbstract:
The effects on cellular proliferation and Ca2+ mobilization of analogues of cyclic AMP (cAMP) and cyclic GMP (cGMP) and of agents that elevate the intracellular concentrations of cyclic nucleotides were compared in closely similar preparations of first-passage rabbit aortic vascular smooth-muscle cells. Proliferation induced by foetal-bovine serum was inhibited by 78% by 1 mM-8-bromo cAMP and by 42% by 1 mM-8-bromo cGMP. In the presence of 100 microM-isobutylmethylxanthine, 100 microM-forskolin increased intracellular cAMP concentration 5-fold and inhibited proliferation by 87%, but did not affect cGMP concentration or cell viability (ATP concentration). Similarly in the presence of 100 microM-isobutylmethylxanthine, 1 mM-SIN-1 (3-morpholinosydnonimine) elevated cGMP concentration 4-fold and inhibited proliferation by 48%, but did not affect cAMP or ATP concentration. Isobutylmethylxanthine (1 mM) elevated cAMP concentration by 3-fold and cGMP concentration by 20-fold and inhibited proliferation by 81%. Concentrations of 8-bromo cAMP, 8-bromo cGMP, forskolin or SIN-1 that inhibited proliferation did not affect the elevation of intracellular free Ca2+ concentration caused by 2% (v/v) foetal-bovine serum, 100 nM-5-hydroxytryptamine or 10 nM-angiotensin II. The results demonstrate that elevation of intracellular cAMP and cGMP concentrations both independently inhibit vascular smooth-muscle cell proliferation, but these effects on proliferation are not mediated by inhibition of Ca2+ mobilization.
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Cornwell, T. L., E. Arnold, N. J. Boerth, and T. M. Lincoln. "Inhibition of smooth muscle cell growth by nitric oxide and activation of cAMP-dependent protein kinase by cGMP." American Journal of Physiology-Cell Physiology 267, no. 5 (November 1, 1994): C1405—C1413. http://dx.doi.org/10.1152/ajpcell.1994.267.5.c1405.
Full textAbstract:
Recent studies indicate that nitric oxide (NO) and guanosine 3',5'-cyclic monophosphate (cGMP) may inhibit the proliferation of vascular smooth muscle cells (SMC) in vitro. The purpose of this study was to investigate the mechanism of NO- and cGMP-dependent inhibition of cultured rat aortic SMC. The cytokine interleukin-1 beta (IL-1 beta) inhibited serum- and platelet-derived growth factor-stimulated [3H]thymidine incorporation into DNA in subcultured rat aortic SMC. Incubation with IL-1 beta for 24 h markedly increased cGMP levels but not adenosine 3',5'-cyclic monophosphate (cAMP) levels. However, the IL-1 beta-induced increase in cGMP was correlated with an activation of the cAMP-dependent protein kinase (cAMP kinase) activity ratio. The activation of the cAMP kinase was prevented by treatments that blocked NO and cGMP production. The NO-generating vasodilator, S-nitroso-N-acetylpenicillamine (SNAP) also inhibited DNA synthesis and elevated cGMP levels. The inhibition of DNA synthesis by both IL-1 beta and SNAP was observed only when cGMP levels were elevated to high levels (10-fold or more). As was the case for IL-1 beta, SNAP increased the activity ratio of cAMP kinase. Selective inhibition of cAMP kinase using (R)-p-bromoadenosine 3',5'-cyclic monophosphorothioate prevented the inhibition of proliferation by IL-1 beta. By contrast, the inhibitor of the cGMP-dependent protein kinase, (R)-p-bromoguanosine 3',5'-cyclic monophosphorothioate, had no effect on IL-1 beta-induced inhibition of cellular proliferation. These studies suggest that cGMP-dependent activation of the cAMP kinase may be responsible in part at least for the NO-dependent inhibition of proliferation of subcultured rat aortic SMC.
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Chakder, S., and S. Rattan. "Involvement of cAMP and cGMP in relaxation of internal anal sphincter by neural stimulation, VIP, and NO." American Journal of Physiology-Gastrointestinal and Liver Physiology 264, no. 4 (April 1, 1993): G702—G707. http://dx.doi.org/10.1152/ajpgi.1993.264.4.g702.
Full textAbstract:
We examined simultaneous changes in resting tension and tissue levels of the two second messengers, adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP), in the opossum internal anal sphincter (IAS). The influence of the nonadrenergic noncholinergic (NANC) nerve stimulation (NS) by electrical field stimulation (EFS) and the putative neurotransmitters nitric oxide (NO) and vasoactive intestinal peptide (VIP) on the above modalities was investigated. The fall in resting IAS tension in response to NS, NO, and VIP was accompanied by significant rises in both cGMP and cAMP. This fall and the levels of cAMP and cGMP were dependent on the intensity of EFS and the concentration of VIP and NO. EFS (2 Hz) caused a 63.5% fall of the resting tension with 61.7 and 118.2% rise of the tissue levels of cAMP and cGMP, respectively (P < 0.05). VIP (1 x 10(-6) M) caused an 81.5% fall of resting tension and 64.2 and 87.0% increases in cAMP and cGMP, respectively. Similarly, NO (1 x 10(-6) M) caused 69.6% fall in tension and an accompanying 93.4 and 415.9% rise of cAMP and cGMP, respectively. Although EFS, VIP, and NO all lowered IAS tension and raised both cyclic nucleotides, the changes in cAMP and cGMP in the IAS are otherwise stimulus specific, since fall in IAS tension by calcitonin gene-related peptide has been shown to be associated with an increase in cAMP without any change in cGMP, whereas the reverse was the case with atrial natriuretic factor. The common second messenger systems in IAS relaxation with NS, VIP, and NO suggest the involvement of VIP and NO as inhibitory neurotransmitters.
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Sadek, Mirna S., Eleder Cachorro, Ali El-Armouche, and Susanne Kämmerer. "Therapeutic Implications for PDE2 and cGMP/cAMP Mediated Crosstalk in Cardiovascular Diseases." International Journal of Molecular Sciences 21, no. 20 (October 10, 2020): 7462. http://dx.doi.org/10.3390/ijms21207462.
Full textAbstract:
Phosphodiesterases (PDEs) are the principal superfamily of enzymes responsible for degrading the secondary messengers 3′,5′-cyclic nucleotides cAMP and cGMP. Their refined subcellular localization and substrate specificity contribute to finely regulate cAMP/cGMP gradients in various cellular microdomains. Redistribution of multiple signal compartmentalization components is often perceived under pathological conditions. Thereby PDEs have long been pursued as therapeutic targets in diverse disease conditions including neurological, metabolic, cancer and autoimmune disorders in addition to numerous cardiovascular diseases (CVDs). PDE2 is a unique member of the broad family of PDEs. In addition to its capability to hydrolyze both cAMP and cGMP, PDE2 is the sole isoform that may be allosterically activated by cGMP increasing its cAMP hydrolyzing activity. Within the cardiovascular system, PDE2 serves as an integral regulator for the crosstalk between cAMP/cGMP pathways and thereby may couple chronically adverse augmented cAMP signaling with cardioprotective cGMP signaling. This review provides a comprehensive overview of PDE2 regulatory functions in multiple cellular components within the cardiovascular system and also within various subcellular microdomains. Implications for PDE2- mediated crosstalk mechanisms in diverse cardiovascular pathologies are discussed highlighting the prospective use of PDE2 as a potential therapeutic target in cardiovascular disorders.
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Tian, Yuehui, Shang Yang, and Shiqiang Gao. "Advances, Perspectives and Potential Engineering Strategies of Light-Gated Phosphodiesterases for Optogenetic Applications." International Journal of Molecular Sciences 21, no. 20 (October 13, 2020): 7544. http://dx.doi.org/10.3390/ijms21207544.
Full textAbstract:
The second messengers, cyclic adenosine 3′-5′-monophosphate (cAMP) and cyclic guanosine 3′-5′-monophosphate (cGMP), play important roles in many animal cells by regulating intracellular signaling pathways and modulating cell physiology. Environmental cues like temperature, light, and chemical compounds can stimulate cell surface receptors and trigger the generation of second messengers and the following regulations. The spread of cAMP and cGMP is further shaped by cyclic nucleotide phosphodiesterases (PDEs) for orchestration of intracellular microdomain signaling. However, localized intracellular cAMP and cGMP signaling requires further investigation. Optogenetic manipulation of cAMP and cGMP offers new opportunities for spatio-temporally precise study of their signaling mechanism. Light-gated nucleotide cyclases are well developed and applied for cAMP/cGMP manipulation. Recently discovered rhodopsin phosphodiesterase genes from protists established a new and direct biological connection between light and PDEs. Light-regulated PDEs are under development, and of demand to complete the toolkit for cAMP/cGMP manipulation. In this review, we summarize the state of the art, pros and cons of artificial and natural light-regulated PDEs, and discuss potential new strategies of developing light-gated PDEs for optogenetic manipulation.
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Parfenova, H., M. Shibata, S. Zuckerman, R. Mirro, and C. W. Leffler. "Cyclic nucleotides and cerebrovascular tone in newborn pigs." American Journal of Physiology-Heart and Circulatory Physiology 265, no. 6 (December 1, 1993): H1972—H1982. http://dx.doi.org/10.1152/ajpheart.1993.265.6.h1972.
Full textAbstract:
Relationships between cyclic nucleotides and cerebrovascular tone were investigated using closed cranial windows in anesthetized newborn pigs. Pial arteriolar diameter was monitored and cerebrospinal fluid (CSF) was collected from beneath the cranial window. Adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) concentrations in CSF were 1,690 +/- 200 and 730 +/- 40 fmol/ml, respectively. Topically applied isozyme-selective and nonselective inhibitors [3-isobutyl-1-methylxanthine (IBMX), theophylline, Ro 201724, dipyridamole, zaprinast, calmidazolium, and W-7] of cyclic nucleotide phosphodiesterases dilated pial arterioles with concomitant increases in cAMP and/or cGMP levels in CSF. Topical application of dibutyryl-cAMP and dibutyryl-cGMP also resulted in pial arteriolar dilation. Ten-minute hypercapnia, which results in pial arteriolar dilation, increased cAMP to 5,240 +/- 900 and cGMP to 1,350 +/- 200 fmol/ml. IBMX and zaprinast potentiated the increases in cAMP and cGMP as well as the cerebrovascular dilation in response to hypercapnia. These data suggest that cyclic nucleotides contribute to regulation of cerebral vascular tone during control conditions. Furthermore, cAMP and/or cGMP appears to be involved in arterial vasodilation in response to hypercapnia in newborn pigs.
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Kokate, T. G., J. A. Heiny, and N. Sperelakis. "Stimulation of the slow calcium current in bullfrog skeletal muscle fibers by cAMP and cGMP." American Journal of Physiology-Cell Physiology 265, no. 1 (July 1, 1993): C47—C53. http://dx.doi.org/10.1152/ajpcell.1993.265.1.c47.
Full textAbstract:
The effects of adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) on slow calcium currents (ICa) were investigated using the Vaseline-gap voltage-clamp technique in bullfrog skeletal muscle cut fibers. Both cAMP and cGMP induced a pronounced increase in the amplitude of ICa when applied to the cut ends of fibers. Both cyclic nucleotides also decreased time to peak current at all membrane potentials. The current-voltage relationship was shifted toward more negative potentials by cAMP as well as cGMP. The potentiating effects of cAMP and cGMP on ICa were additive. 8-Bromo analogues of both nucleotides had similar effects on ICa. The beta-adrenergic agonist isoproterenol, applied extracellularly, also produced an increase in the amplitude of ICa and produced a leftward shift in the current-voltage relationship. These results suggest that both cAMP and cGMP modulate calcium slow channels in bullfrog skeletal muscle fibers, causing stimulation of the ICa. The effect of cyclic nucleotides on ICa in bullfrog skeletal muscle contrasts with that in mammalian cardiac muscle, in which the same nucleotides produce opposite effects on the slow ICa, i.e., in cardiac muscle cAMP stimulates, and cGMP inhibits, the slow ICa.
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El-Daher, Samer S., Martin Eigenthaler, Ulrich Walter, Teiichi Furuichi, Atsushi Miyawaki, Mikoshiba Mikoshiba, Vijay V. Kakkar, and Kalwant S. Authi. "Distribution and Activation of cAMP- and cGMP-Dependent Protein Kinases in Highly Purified Human Platelet Plasma and Intracellular Membranes." Thrombosis and Haemostasis 76, no. 06 (1996): 1063–71. http://dx.doi.org/10.1055/s-0038-1650707.
Full textAbstract:
SummaryPreviously cAMP- and cGMP-dependent protein kinases (cAMP-PK, cGMP-PK) have been found predominantly associated with the particulate fraction in human platelets. We now report the distribution and activation of cAMP-PK and cGMP-PK in highly purified fractions of human platelet plasma (PM) and intracellular membranes (IM) prepared using high voltage free flow electrophoresis. Two non-hydrolys-able analogues of cAMP and cGMP namely Sp-5,6-DCl-cBiMPS and 8-p-CPT-cGMP have been used to activate cAMP-PK and cGMP-PK respectively. Addition of either agonist with [γ32P]ATP stimulated the endogenous activity of cAMP-PK or cGMP-PK in PM but not in IM. With PM Sp-5,6-DCl-cBiMPS stimulated the phosphorylation of protein substrates of Mr 16,22,24,46-50,66,90,160 and 250 kDa. A specific peptide inhibitor of cAMP-PK inhibited the phosphorylation of all of the substrates by Sp-5,6-DCl-cBiMPS. 8-pCPT-cGMP also induced the phosphorylation of a number of substrates particularly 16,22, 46-50, 90 and 250 kDa proteins. Inclusion of the cAMP-PK inhibitor peptide totally blocked the phosphorylation of the 16 and 22 kDa proteins, partially inhibited phosphorylation of 46-50 and 90 kDa proteins and had no effect on the 250 kDa protein indicating the 46-50, 90 and 250 kDa proteins were also cGMP-PK substrates. Western blotting with antibodies to cGMP-PK and the catalytic subunit of cAMP-PK revealed the presence of the kinases to be exclusively associated with PM with no detection in IM.The presence of cAMP-PK substrates in IM was investigated by exogenous addition of catalytic subunit of cAMP-PK. Phosphoproteins of Mr 16, 22, 27, 30,45, 75,116 and 250 kDa were detected. A range of antibodies to cAMP-PK substrates were used to identify and localise the substrates. These antibodies revealed GPIb and VASP to be exclusively associated with PM fractions. Rap IB was also predominantly associated with PM with a small level detected in IM. Antibodies to the IP3 receptor (18A10 and 4C11) revealed the protein to be predominantly associated with IM. Additionally the antibody 4C11 recognised a 230 kDa protein band in PM that was not seen in IM. From the known specificity of these antibodies the results confirm the presence of a type IIP3 receptor in IM and a distinct (possible type III) IP3 receptor with the PM. the 16, 22, 27, 30, 75 and 116 kDa proteins in IM represent nwly detected substartes for camp-pk of presently unknown identity.
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Gupta, Mahesh P., Michael D. Ober, Carolyn Patterson, Mohammed Al-Hassani, Viswanathan Natarajan, and C. Michael Hart. "Nitric oxide attenuates H2O2-induced endothelial barrier dysfunction: mechanisms of protection." American Journal of Physiology-Lung Cellular and Molecular Physiology 280, no. 1 (January 1, 2001): L116—L126. http://dx.doi.org/10.1152/ajplung.2001.280.1.l116.
Full textAbstract:
Nitric oxide (·NO) attenuates hydrogen peroxide (H2O2)-mediated injury in porcine pulmonary artery endothelial cells (PAECs) and modulates intracellular levels of cGMP and cAMP. We hypothesized that ·NO attenuates H2O2-induced PAEC monolayer barrier dysfunction through cyclic nucleotide-dependent signaling mechanisms. To examine this hypothesis, cultured PAEC monolayers were treated with H2O2, and barrier function was measured as transmonolayer albumin clearance. H2O2caused significant PAEC barrier dysfunction that was attenuated by intracellular as well as extracellular ·NO generation. ·NO increased PAEC cGMP and cAMP levels, but treatment with inhibitors of soluble guanylate cyclase or protein kinase G did not abrogate ·NO-mediated barrier protection. In contrast, H2O2decreased protein kinase A activity, and inhibiting protein kinase A abrogated the protective effect of ·NO. H2O2-induced barrier dysfunction was not associated with decreased levels of cGMP or cAMP. 3-Isobutyl-1-methylxanthine and the cGMP analog 8-bromo-cGMP had little effect on H2O2-mediated endothelial barrier dysfunction, whereas 8-bromo-cAMP plus 3-isobutyl-1-methylxanthine was protective. These results indicate that ·NO modulates vascular endothelial barrier function through cAMP-dependent signaling mechanisms.
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Wyatt, Todd A., Mary A. Forgèt, Jennifer M. Adams, and Joseph H. Sisson. "Both cAMP and cGMP are required for maximal ciliary beat stimulation in a cell-free model of bovine ciliary axonemes." American Journal of Physiology-Lung Cellular and Molecular Physiology 288, no. 3 (March 2005): L546—L551. http://dx.doi.org/10.1152/ajplung.00107.2004.
Full textAbstract:
Previously, we have shown that the ATPase-dependent motion of cilia in bovine bronchial epithelial cells (BBEC) can be regulated through the cyclic nucleotides, cAMP via the cAMP-dependent protein kinase (PKA) and cGMP via the cGMP-dependent protein kinase (PKG). Both cyclic nucleotides cause an increase in cilia beat frequency (CBF). We hypothesized that cAMP and cGMP may act directly at the level of the ciliary axoneme in BBEC. To examine this, we employed a novel cell-free system utilizing detergent-extracted axonemes. Axoneme movement was whole-field analyzed digitally with the Sisson-Ammons video analysis system. A suspension of extracted axonemes remains motionless until the addition of 1 mM ATP that establishes a baseline CBF similar to that seen when analyzing intact ciliated BBEC. Adding 10 μM cAMP or 10 μM cGMP increases CBF beyond the established ATP baseline. However, the cyclic nucleotides did not stimulate CBF in the absence of ATP. Therefore, the combination of cAMP and cGMP augments ATP-driven CBF increases at the level of isolated axoneme.
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Tang, K. M., J. L. Sherwood, and R. J. Haslam. "Photoaffinity labelling of cyclic GMP-binding proteins in human platelets." Biochemical Journal 294, no. 2 (September 1, 1993): 329–33. http://dx.doi.org/10.1042/bj2940329.
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The photoaffinity labelling of platelet cyclic GMP (cGMP)-binding proteins by [32P]cGMP was studied; at least five labelled proteins (110, 80, 55, 49 and 38 kDa) were detected in platelet cytosol and four (80, 65, 49 and 38 kDa) in platelet membranes. The 110 kDa species was identified as cGMP-inhibited cyclic AMP (cAMP) phosphodiesterase (PDE III) by immunoprecipitation and by the inhibition of photolabelling by specific inhibitors of this enzyme. Similarly, the 80 kDa species was identified as cGMP-dependent protein kinase by immunoprecipitation and by the effects of cGMP analogues on photolabelling. Addition of cAMP greatly enhanced the labelling of this 80 kDa protein, implying the existence of a potentially important interaction between the effects of cGMP and cAMP. The 65 kDa photolabelled protein appears to be a novel platelet cyclic-nucleotide-binding protein. In contrast, the 49 and 55 kDa photolabelled species are probably the RI and RII regulatory subunits of cAMP-dependent protein kinase, and the 38 kDa protein(s) may be proteolytic fragment(s) of RI and/or RII.
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Yamaki, M., S. McIntyre, M. E. Rassier, J. H. Schwartz, and T. P. Dousa. "Cyclic 3',5'-nucleotide diesterases in dynamics of cAMP and cGMP in rat collecting duct cells." American Journal of Physiology-Renal Physiology 262, no. 6 (June 1, 1992): F957—F964. http://dx.doi.org/10.1152/ajprenal.1992.262.6.f957.
Full textAbstract:
We studied cyclic 3',5'-nucleotide phosphodiesterase (PDE) isozymes and their role in adenosine 3',5'-cyclic monophosphate (cAMP) and cGMP metabolism in a rat inner medullary collecting duct (IMCD) cell line. The homogenized and fractionated IMCD cells of cAMP-PDE and all of cGMP-PDE activity were found in the cytosol. The majority of cytosolic cAMP-PDE (greater than 50%) was isozyme PDE-IV; the Ca(2+)-calmodulin-sensitive PDE-I was present only in cytosol. Preincubation of IMCD cells with PDE-IV inhibitor rolipram markedly (5x) enhanced levels of cAMP both basal and in the presence of [Arg8]vasopressin (AVP). Cilostamide (for PDE-III) or vinpocetine had no effect, whereas PDE-I inhibitor 8-methoxymethyl-3-isobutyl-1-methylxanthine (8-MeoM-IBMX) enhanced AVP-dependent cAMP levels. Exposure of IMCD cells to 2 microM ionomycin decreased both basal and AVP-stimulated cAMP. Depletion of Ca2+ by preincubation of IMCD cells in the Ca(2+)-free medium with ethylene glycol-bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid markedly enhanced the stimulatory response of cAMP to AVP, and addition of 8-MeoM-IBMX further enhanced the AVP response. The levels of cGMP, basal or in response to atriopeptin (ANP), were not affected by PDE-V inhibitor zaprinast, but both inhibitors of PDE-I, 8-MeoM-IBMX and vinpocetine, increased basal cGMP, and 8-MeoM-IBMX also increased cGMP levels enhanced by ANP. The depletion of Ca2+ from IMCD cells alone had no effect on cGMP levels, but effects of 8-MeoM-IBMX and vinpocetine on the ANP-stimulated cGMP levels were enhanced.(ABSTRACT TRUNCATED AT 250 WORDS)
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Zhang, Qihang, Michael Lazar, Bruno Molino, Roberto Rodriguez, Tomer Davidov, Jun Su, James Tse, Harvey R. Weiss, and Peter M. Scholz. "Reduction in interaction between cGMP and cAMP in dog ventricular myocytes with hypertrophic failure." American Journal of Physiology-Heart and Circulatory Physiology 289, no. 3 (September 2005): H1251—H1257. http://dx.doi.org/10.1152/ajpheart.01234.2003.
Full textAbstract:
Baseline function and signal transduction are depressed in hearts with hypertrophic failure. We tested the hypothesis that the effects of cGMP and its interaction with cAMP would be reduced in cardiac myocytes from hypertrophic failing hearts. Ventricular myocytes were isolated from control dogs, dogs with aortic valve stenosis hypertrophy, and dogs with pacing hypertrophic failure. Myocyte function was measured using a video edge detector. Cell contraction data were obtained at baseline, with 8-bromo-cGMP (10−7, 10−6, and 10−5 M), with erythro-9-(2-hydroxy-3-nonyl)adenine [EHNA; a cAMP phosphodiesterase (PDE2) inhibitor] plus 8-bromo-cGMP, or milrinone (a PDE3 inhibitor) plus 8-bromo-cGMP. Baseline percent shortening and maximal rates of shortening (Rmax) and relaxation were slightly reduced in hypertrophic myocytes and were significantly lower in failing myocytes (Rmax: control dogs, 95.3 ± 17.3; hypertrophy dogs, 88.2 ± 5.5; failure dogs, 53.2 ± 6.4 μm/s). 8-Bromo-cGMP dose dependently reduced myocyte function in all groups. However, EHNA (10−6 M) and milrinone (10−6 M) significantly reduced the negative effects of cGMP on cell contractility in control and hypertrophy but not in failing myocytes (Rmax for control dogs: cGMP, −46%; +EHNA, −21%; +milrinone, −19%; for hypertrophy dogs: cGMP, −40%; +EHNA, −13%; +milrinone, −20%; for failure dogs: cGMP, −40%; +EHNA, −29%; +milrinone, −32%). Both combinations of EHNA-cGMP and milrinone-cGMP significantly increased intracellular cAMP in control, hypertrophic, and failing myocytes. These data indicated that the cGMP signaling pathway was preserved in hypertrophic failing cardiac myocytes. However, the interaction of cGMP with the cAMP signaling pathway was impaired in these failing myocytes.
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Sirotkin, A. V. "Inter-relationships between nonapeptide hormones and cyclic nucleotides within cultured porcine granulosa cells." Journal of Endocrinology 150, no. 2 (August 1996): 343–48. http://dx.doi.org/10.1677/joe.0.1500343.
Full textAbstract:
Abstract The reciprocal control of nonapeptide hormone (oxytocin, vasopressin) and cyclic nucleotide (cAMP, cGMP) release by porcine granulosa cells was studied. In particular, the influence of vasopressin and oxytocin treatment (10–10 000 ng/ml) on basal and LH-induced cAMP and cGMP output, as well as the effects of dibutyryl cAMP (dbcAMP; cAMP analogue) and forskolin (a stimulator of cAMP formation; 0·1–1000 ng/ml) on vasopressin and oxytocin secretion by cultured porcine granulosa cells were examined. It was observed that the addition of arginine-8-vasopressin or oxytocin stimulated both cAMP and cGMP output from granulosa cells. Moreover, both vasopressin and oxytocin also increased LH-stimulated cAMP and cGMP release. On the other hand, both dbcAMP and forskolin decreased vasopressin secretion. Oxytocin release was stimulated under the influence of dbcAMP. The same stimulating effect occurred with forskolin given at a low dose (1 ng/ml), whilst higher doses of forskolin (10 or 1000 ng/ml) were inhibitory. The present observations demonstrate the reciprocal influence of nonapeptide hormones and cyclic nucleotides in porcine ovarian cells. Oxytocin and vasopressin, like LH, exert their action on the ovary via the activation of cAMP- and cGMP-dependent intracellular mechanisms. cAMP in turn inhibits vasopressin release through a negative feedback mechanism. On the other hand, a reciprocal stimulation of oxytocin and cAMP output in granulosa cells is suggested. Thus, cyclic nucleotides can be both regulators of nonapeptide hormone secretion and mediators of their action within porcine ovaries. Journal of Endocrinology (1996) 150, 343–348
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Dhanakoti, Srinivas N., Yuansheng Gao, Minh Q. Nguyen, and J. Usha Raj. "Involvement of cGMP-dependent protein kinase in the relaxation of ovine pulmonary arteries to cGMP and cAMP." Journal of Applied Physiology 88, no. 5 (May 1, 2000): 1637–42. http://dx.doi.org/10.1152/jappl.2000.88.5.1637.
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Agonist-induced smooth muscle relaxation occurs following an increase in intracellular concentrations of cGMP or cAMP. However, the role of protein kinase G (PKG) and/or protein kinase A (PKA) in cGMP- or cAMP-mediated pulmonary vasodilation is not clearly elucidated. In this study, we examined the relaxation responses of isolated pulmonary arteries of lambs (age = 10 ± 1 days), preconstricted with endothelin-1, to increasing concentrations of 8-bromo-cGMP (8-BrcGMP) or 8-BrcAMP (cell-permeable analogs), in the presence or absence of Rp-8-β-phenyl-1, N 2-etheno-bromoguanosine cyclic monosphordthioate ( Rp-8-PET-BrcGMPS) or KT-5720, selective inhibitors of PKG and PKA, respectively. When examined for specificity, Rp-8-Br-PET-cGMPS abolished PKG, but not PKA, activity in pulmonary arterial extracts, whereas KT-5720 inhibited PKA activity only. 8-BrcGMP-induced relaxation was inhibited by the PKG inhibitor only, whereas 8-BrcAMP-induced relaxation was inhibited by both inhibitors. A nearly fourfold higher concentration of cAMP than cGMP was required to relax arteries by 50% and to activate PKG by 50%. Our results demonstrate that relaxation of pulmonary arteries is more sensitive to cGMP than cAMP and that PKG plays an important role in both cGMP- and cAMP-mediated relaxation.
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Kruuse, C., E. Frandsen, S. Schifter, LL Thomsen, S. Birk, and J. Olesen. "Plasma Levels of cAMP, cGMP and CGRP in Sildenafil-Induced Headache." Cephalalgia 24, no. 7 (July 2004): 547–53. http://dx.doi.org/10.1111/j.1468-2982.2003.00712.x.
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Sildenafil, a selective inhibitor of the cyclic guanosine monophosphate (cGMP) degrading phosphodiestrase 5 (PDE5), induced migraine without aura in 10 of 12 migraine patients and in healthy subjects it induced significantly more headache than placebo. The aim of the present study was to determine whether the pain-inducing effects of sildenafil would be reflected in plasma levels of important signalling molecules in migraine: cGMP, cyclic adenosine monophosphate (cAMP) and calcitonin gene-related peptide (CGRP). Ten healthy subjects (four women, six men) and 12 patients (12 women) suffering from migraine without aura were included in two separate double-blind, placebo-controlled, cross-over studies in which placebo or sildenafil 100 mg was administered orally. Plasma levels of CGRP, cAMP and cGMP were determined in blood from the antecubital vein. Despite the ability of sildenafil to induce headache and migraine, no significant differences in plasma levels of CGRP, cGMP and cAMP were detected after sildenafil compared with placebo. In conclusion, plasma levels of CGRP, cGMP and cAMP remain normal during sildenafil-induced headache or migraine. However, since previous studies indicate an important role of these signalling molecules, the present study questions whether cAMP and cGMP in peripheral blood can be used for monitoring pathophysiological events in headache and migraine mechanisms.
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Steiner, Alexandre A., Maria J. A. Rocha, and Luiz G. S. Branco. "A neurochemical mechanism for hypoxia-induced anapyrexia." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 283, no. 6 (December 1, 2002): R1412—R1422. http://dx.doi.org/10.1152/ajpregu.00328.2002.
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Hypoxia evokes a regulated decrease in body temperature, a response that has been termed anapyrexia, but the mechanisms involved are poorly understood. Therefore, the present study was undertaken to test the hypothesis that hypoxia-induced anapyrexia results from the activation of cAMP- and cGMP-dependent pathways in the preoptic region (PO). Adult male Wistar rats weighing 230–260 g were used. Body temperature was monitored by biotelemetry, and the levels of cAMP and cGMP were determined in the anteroventral third ventricular region (AV3V), where the PO is located. Using immunohistochemistry, we observed that the PO contains a high density of cAMP- and cGMP-containing cells. Interestingly, hypoxia exposure raised the levels of cAMP and cGMP in the AV3V. Intra-PO microinjection of Rp-cAMPS, an inhibitor of cAMP-dependent protein kinase, attenuated hypoxia-induced anapyrexia. Similarly, intra-PO microinjection of the mixed β-adrenoceptor/serotonin (5-HT1A) receptor antagonist propranolol also impaired the drop in body temperature in response to hypoxia. The reduction in body temperature evoked by intra-PO serotonin, but not epinephrine, was blocked by Rp-cAMPS, indicating the involvement of a preoptic serotonin-cAMP pathway in the development of anapyrexia. Moreover, microinjection of N G-monomethyl-l-arginine, an inhibitor of nitric oxide (NO) synthesis, or Rp-cGMPS, an inhibitor of cGMP-dependent protein kinase, into the PO also attenuated hypoxia-induced anapyrexia. In conclusion, the present study supports that hypoxia-induced anapyrexia results from the activation of the serotonin-cAMP and NO-cGMP pathways in the PO.
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Guimaraes, Danielle, Rafael Portella, Christelle Kamga-Pride, Jose Eduardo Tanus-Santos, and Sruti Shiva. "Nitrite Differently Activates cGMP versus cAMP." Free Radical Biology and Medicine 112 (November 2017): 164–65. http://dx.doi.org/10.1016/j.freeradbiomed.2017.10.255.
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Zaccolo, Manuela, and Matthew A. Movsesian. "cAMP and cGMP Signaling Cross-Talk." Circulation Research 100, no. 11 (June 8, 2007): 1569–78. http://dx.doi.org/10.1161/circresaha.106.144501.
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Vettel, C., S. Lämmle, S. Ewens, C. Cervirgen, J. Emons, A. Ongherth, M. Dewenter, et al. "PDE2-mediated cAMP hydrolysis accelerates cardiac fibroblast to myofibroblast conversion and is antagonized by exogenous activation of cGMP signaling pathways." American Journal of Physiology-Heart and Circulatory Physiology 306, no. 8 (April 15, 2014): H1246—H1252. http://dx.doi.org/10.1152/ajpheart.00852.2013.
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Recent studies suggest that the signal molecules cAMP and cGMP have antifibrotic effects by negatively regulating pathways associated with fibroblast to myofibroblast (MyoCF) conversion. The phosphodiesterase 2 (PDE2) has the unique property to be stimulated by cGMP, which leads to a remarkable increase in cAMP hydrolysis and thus mediates a negative cross-talk between both pathways. PDE2 has been recently investigated in cardiomyocytes; here we specifically addressed its role in fibroblast conversion and cardiac fibrosis. PDE2 is abundantly expressed in both neonatal rat cardiac fibroblasts (CFs) and cardiomyocytes. The overexpression of PDE2 in CFs strongly reduced basal and isoprenaline-induced cAMP synthesis, and this decrease was sufficient to induce MyoCF conversion even in the absence of exogenous profibrotic stimuli. Functional stress-strain experiments with fibroblast-derived engineered connective tissue (ECT) demonstrated higher stiffness in ECTs overexpressing PDE2. In regard to cGMP, neither basal nor atrial natriuretic peptide-induced cGMP levels were affected by PDE2, whereas the response to nitric oxide donor sodium nitroprusside was slightly but significantly reduced. Interestingly, despite persistently depressed cAMP levels, both cGMP-elevating stimuli were able to completely prevent the PDE2-induced MyoCF phenotype, arguing for a double-tracked mechanism. In conclusion, PDE2 accelerates CF to MyoCF conversion, which leads to greater stiffness in ECTs. Atrial natriuretic peptide- and sodium nitroprusside-mediated cGMP synthesis completely reverses PDE2-induced fibroblast conversion. Thus PDE2 may augment cardiac remodeling, but this effect can also be overcome by enhanced cGMP. The redundant role of cAMP and cGMP as antifibrotic meditators may be viewed as a protective mechanism in heart failure.
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Rodriguez, Roberto, Bruno Molino, Harvey R. Weiss, and Peter M. Scholz. "Negative metabolic and coronary flow effects of decreases in cAMP and increases in cGMP in control and renal hypertensive rabbit hearts." Journal of Applied Physiology 97, no. 1 (July 2004): 439–45. http://dx.doi.org/10.1152/japplphysiol.01115.2003.
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The interaction during stimulation of cGMP and inhibition of cAMP was investigated in control and renal hypertensive hearts. Control and hypertensive [1 kidney, 1 clip (1K1C)] rabbits were used. The anesthetized open-chest groups were vehicle, 8-bromo-cGMP (8-Br-cGMP; 10−3M), propranolol (Prop; 2 mg/kg), and Prop + 8-Br-cGMP. O2 consumption levels (V̇o2) in the subepicardium (Epi) and subendocardium (Endo) were determined from coronary flow (microspheres) and O2 extraction (microspectrophotometry). Wall thickening and cAMP levels were also determined. In control, no significant change in V̇o2 was seen for the 8-Br-cGMP group, but V̇o2 was decreased from Epi (9.7 ± 1.5 ml O2·min−1·100 g−1) and Endo (10.5 ± 0.4 ml O2·min−1·100 g−1) to 6.8 ± 0.6/7.8 ± 0.5 ml O2·min−1·100 g−1 in the control Prop group. Control Prop + 8-Br-cGMP did not cause a further fall in V̇o2 but lowered Endo flow. In 1K1C, V̇o2 decreased from Epi/Endo (10.8 ± 1.3/11 ± 1.0 ml O2·min−1·100 g−1) to 7.8 ± 1.1/8.7 ± 0.5 ml O2·min−1·100 g−1 in the 1K1C 8-Br-cGMP group and to 7 ± 0.5/8.1 ± 0.5 ml O2·min−1·100 g−1 in the 1K1C Prop group. 1K1C Prop + 8-Br-cGMP did not cause a further fall in V̇o2 but lowered blood flow. No significant changes in cAMP levels were present with 8-Br-cGMP in control or 1K1C rabbits, but significant decreases were seen with Prop in both control and 1K1C rabbits. No further change was seen in Prop + 8-Br-cGMP for either control or 1K1C. Thus the negative metabolic effect of stimulating cGMP was seen only in the hypertensive rabbit heart. The negative metabolic effect of inhibiting cAMP was seen in both the control and the hypertensive rabbit heart. However, the negative metabolic effects of cGMP and cAMP were nonadditive.
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Wang, Q., J. Bryowsky, R. D. Minshall, and D. A. Pelligrino. "Possible obligatory functions of cyclic nucleotides in hypercapnia-induced cerebral vasodilation in adult rats." American Journal of Physiology-Heart and Circulatory Physiology 276, no. 2 (February 1, 1999): H480—H487. http://dx.doi.org/10.1152/ajpheart.1999.276.2.h480.
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Current evidence suggests that nitric oxide (NO) and vasodilating prostanoids, possibly via the actions of cGMP and cAMP, play permissive roles in hypercapnic cerebral vasodilation. The present study examined whether cGMP and cAMP have obligatory functions in hypercapnia. Using a closed cranial window in adult rats, we measured pial arteriolar diameters and periarachnoid cerebrospinal fluid (pCSF) cyclic nucleotide levels during normo- and hypercapnia and in the presence or absence of inhibitors of neuronal NO synthase (nNOS) or cyclooxygenase (COX). Also, we measured cGMP and cAMP contents in primary neuronal and astrocyte cultures, at different levels of CO2. Hypercapnia (arterial[Formula: see text] 65 mmHg)-induced pial arteriolar dilation was accompanied by 70–80% elevations in pCSF cGMP and cAMP. Inhibition of nNOS with 7-nitroindazole (7-NI) significantly reduced both the CO2-induced arteriolar dilation (by 77%) and the pCSF cGMP and cAMP increases (by 60–70%). Inhibition of COX with indomethacin reduced arteriolar CO2 reactivity (by 83%) and pCSF cyclic nucleotide increases (by 80–100%). In neuronal cultures a transient NO-dependent increase in cGMP, but not cAMP, was seen when the CO2 level was raised from 5 to 14%. No changes were seen in astrocytes. The 7-NI and indomethacin-inhibitable increases in pial arteriolar diameter and cyclic nucleotide production during hypercapnia suggest a link between these two responses. One possible, although not exclusive, interpretation of these findings is that the cyclic nucleotides have an obligatory function in the CO2response. The large overlap in the abilities of nNOS and COX inhibitors to elicit those effects further implies interactions (“cross talk”) between the cGMP and cAMP vasodilating pathways. The in vitro data suggest that hypercapnia stimulates NO production in neurons.
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Magness, R. R., C. R. Rosenfeld, A. Hassan, and P. W. Shaul. "Endothelial vasodilator production by uterine and systemic arteries. I. Effects of ANG II on PGI2 and NO in pregnancy." American Journal of Physiology-Heart and Circulatory Physiology 270, no. 6 (June 1, 1996): H1914—H1923. http://dx.doi.org/10.1152/ajpheart.1996.270.6.h1914.
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Uterine vasculature is less responsive than systemic vasculature to angiotensin II (ANG II)-induced vasoconstriction. We hypothesized that pregnancy augments basal and ANG II-stimulated endothelial prostacyclin (PGI2) and/or nitric oxide (NO) production, which locally increase vascular smooth muscle (VSM) adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP), respectively. Uterine (UA) and systemic arteries (SA) from pregnant (P) and nonpregnant (NP) sheep were incubated with isobutylmethylxanthine. Basal PGI2, cAMP, and cGMP production was 2.4-, 1.6-, and 5.9-fold greater (P < 0.01) in UA from P vs. NP sheep; endothelium removal lowered (P < 0.05) values 69, 44, and 88%. Basal SA PGI2 and cAMP, but not cGMP, also were elevated by pregnancy. Indomethacin (Indo; 100 microM) decreased PGI2 and cAMP, but not cGMP production; N omega-nitro-L-arginine methyl ester (L-NAME; 10 microM) and methylene blue (MB, 10 microM) only decreased cGMP. Basal UA, but not SA, NO synthase activity (conversion of [3H]arginine to [3H]citrulline), was 1.8-fold higher in pregnancy and decreased (P < 0.01) after endothelium removal and with L-NAME. ANG II (50 nM) increased PGI2 (86%) and cAMP (56%) production only in UA from P sheep (P < 0.05); this was abolished by endothelium removal or Indo. ANG II also increased (P < 0.01) cGMP production by UA from both groups but only by SA from P ewes; this was absent in denuded, L-NAME-, or MB-treated vessels. Stimulation of VSM cGMP production with sodium nitroprusside (50 microM) was inhibited by MB, but not L-NAME or endothelium removal. In pregnancy, endothelial PGI2 and NO production are enhanced and may contribute to attenuated ANG II vasoconstriction via VSM cAMP and cGMP.
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Dickinson, Natalie, Elliott Jang, and Richard Haslam. "Cyclic Nucleotides and Phosphodiesterases in Platelets." Thrombosis and Haemostasis 82, no. 08 (1999): 412–23. http://dx.doi.org/10.1055/s-0037-1615861.
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IntroductionIt is now almost 30 years since the discovery that prostaglandin E1 (PGE1) inhibits platelet responses to aggregating agents, together with finding that the effects of this compound are mediated by adenosine 3′, 5′-cyclic monophosphate (cAMP) initiated interest in the physiological and pharmacological regulation of platelet function by other agents that increase platelet cAMP, as reviewed elsewhere.1 The most important agonists that stimulate cAMP formation in platelets have now been identified as prostacyclin (PGI2), prostaglandin D2 (PGD2), and adenosine, which exert their effects through receptors of the serpentine or seven transmembrane segment class (IP, DP and A2 receptors, respectively).2 The latter then stimulate cAMP formation by adenylyl cyclase via the GTP-dependent activation of the G-protein, Gs (Fig. 1). In the classical view, cAMP exerts its effects solely by binding to the RI and RII regulatory subunits of type I and type II cAMP-dependent protein kinases (PKA). The catalytic subunits of the kinases then dissociate and phosphorylate selected serine and threonine residues on target proteins that prevent or reverse platelet activation.2 A crucial role is played by cAMP phosphodiesterases, which degrade cAMP to 5′-AMP, thereby diminishing and terminating the effects of agonists that stimulate cAMP formation (Fig. 1). In early studies, this was demonstrated by the ability of first-generation inhibitors of cAMP phosphodiesterases, particularly the methylxanthines, to inhibit platelet aggregation and potentiate the inhibitory effects of activators of platelet adenylyl cyclase.1 Such studies provided the rationale for the subsequent development of more potent and selective phosphodiesterase inhibitors as potential antithrombotic agents.Interest in the role of guanosine 3′,5′-cyclic monophosphate (cGMP) in platelets closely followed the discovery of the inhibitory action of cAMP. An early hypothesis that cGMP might potentiate platelet aggregation was abandoned by 1978, after it was shown that some inhibitors of platelet aggregation, such as nitroprusside (NP), also increased platelet cGMP.1 It soon emerged that all nitrovasodilators release nitric oxide and activate soluble guanylyl cyclase (GC) and that the cGMP formed stimulates cGMP-dependent protein kinases (PKG) in many cells and tissues (Fig. 1), including vascular smooth muscle and platelets.3 The crucial physiological importance of this pathway was established with the identification of endothelium-derived relaxing factor (EDRF) as nitric oxide.4 cGMP phosphodiesterases play an essential role by limiting increases in cellular cGMP, and inhibition of these enzymes was found to potentiate the effects of nitric oxide and nitric oxide donors on platelets and other cells.5 The ability of cAMP and cGMP to activate distinct protein kinases led to a persistent view that these two cyclic nucleotides operate in parallel and independent ways to inhibit platelet function, cAMP mediating the effects of agonists such as PGI2, and cGMP mediating the effects of nitric oxide.2,3 However, over the last 10 years, considerable evidence has accumulated to indicate that this is not the case in platelets (or in many other cells) and that cross-talk between the cAMP and cGMP systems may occur on at least two levels, affecting both cyclic nucleotide phosphodiesterase (PDE) and protein kinase activities (Fig. 1). One of the most significant of these interactions is through the effects of cGMP on the hydrolysis of cAMP by PDEs. It is the purpose of this chapter to describe platelet PDEs and to discuss how their individual characteristics and regulation may impact platelet function and the design of useful antithrombotic agents. In addition, evidence that both cGMP and cAMP may activate PKG and that these cyclic nucleotides may exert effects in platelets that do not involve either PKA or PKG will be discussed briefly.
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Rybalkin, Sergei, and Karin Bornfeldt. "Cyclic Nucleotide Phosphodiesterases and Human Arterial Smooth Muscle Cell Proliferation." Thrombosis and Haemostasis 82, no. 08 (1999): 424–34. http://dx.doi.org/10.1055/s-0037-1615862.
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IntroductionSmooth muscle cells (SMCs) in the arterial wall are normally found in a contractile, nonproliferative state. These SMCs are continuously exposed to agents that elevate cyclic AMP (cAMP) and cyclic GMP (cGMP), such as prostacyclin and nitric oxide (NO) released from the endothelium. Both cAMP and cGMP potently inhibit SMC proliferation by antagonizing major signaling pathways induced by growth factors, such as platelet-derived growth factor. Different forms of injury to the endothelium result in proliferation of the SMCs and can develop into atherosclerosis, restenosis, or arterial thickening associated with neonatal pulmonary hypertension. In human adult aorta, cAMP and cGMP levels are tightly regulated by synthesis and degradation. The latter is mediated by at least two different cAMP phosphodiesterases (PDEs), PDE3 and PDE4, and three different PDEs that degrade mainly cGMP, PDE1A, PDE1B, and PDE5. Strikingly, expression of a new PDE that degrades both cAMP and cGMP, PDE1C, is markedly induced in proliferating SMCs from the same aorta in culture, whereas its expression is nondetectable in contractile aorta. We propose that, for a human arterial SMC to be able to efficiently proliferate, and perhaps even to undergo a phenotypic change from a quiescent to a proliferative phenotype, it has to efficiently degrade inhibitory cAMP and cGMP. In human SMCs, PDE1C is induced to degrade these cyclic nucleotides. Understanding the role of PDE1C in SMC proliferation may provide the basic information necessary for development of highly specific PDE1C inhibitors that target proliferating SMCs in cardiovascular disease.
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Abdollahi, Mohammad, Foreshteh Mashayekhi, Farzaneh Agha-hoseini, Ali Rezaie, Mohammad J. Zamani, and Reza Khorasani. "Alteration of Cyclic Nucleotides Levels and Oxidative Stress in Saliva of Human Subjects with Periodontitis." Journal of Contemporary Dental Practice 6, no. 4 (2005): 46–53. http://dx.doi.org/10.5005/jcdp-6-4-46.
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Abstract Experimental findings suggest a protective role for cyclic nucleotides against induction of oxidative stress in saliva. Oxidative stress is a major contributor to the pathogenesis of inflammatory diseases. This study was conducted to evaluate salivary oxidative stress along with cGMP and cAMP levels in periodontitis subjects. cAMP and cGMP are second messengers that have important roles in salivary gland functions. Unstimulated whole saliva samples were obtained from periodontitis patients and age- and sex-matched healthy individuals. Saliva samples were analyzed for thiobarbituric reactive substances (TBARS) as a marker of lipid peroxidation, ferric reducing ability (total antioxidant power, TAP), and levels of cAMP and cGMP. Concentrations of cAMP and cGMP were reduced in the saliva of patients with moderate and severe periodontitis. Saliva of patients with severe periodontitis had higher TBARS and lower TAP than control subjects. The presence of oxidative stress and lower levels of salivary cGMP and cAMP in periodontitis are in association with disease severity. Citation Mashayekhi F, Agha-hosseini F, Rezaie A, Zamani MJ, Khorasani R, Abdollahi M. Alteration of Cyclic Nucleotides Levels and Oxidative Stress in Saliva of Human Subjects with Periodontitis. J Contemp Dent Pract 2005 November;(6)4:046-053.
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Haynes, J., P. A. Kithas, A. E. Taylor, and S. J. Strada. "Selective inhibition of cGMP-inhibitable cAMP phosphodiesterase decreases pulmonary vasoreactivity." American Journal of Physiology-Heart and Circulatory Physiology 261, no. 2 (August 1, 1991): H487—H492. http://dx.doi.org/10.1152/ajpheart.1991.261.2.h487.
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Guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP) are mediators of smooth muscle relaxation. In this study, selective inhibitors of phosphodiesterase (PDE) isozymes were used to assess the role of cyclic nucleotide hydrolysis in angiotensin II (ANG II) and hypoxic pulmonary vasoconstriction. In isolated rat lungs, the hypoxic pressor response (HPR) was induced with a 95% N2-5% CO2 gas mixture. When administered during the plateau of the HPR, trequinsin (nonselective PDE inhibitor) and indolidan (cGMP-inhibitable cAMP PDE inhibitor) significantly (P = 0.01) decreased the pulmonary arterial pressure (Ppa) by 60 +/- 7 and 53 +/- 3%, respectively, compared with zaprinast (cGMP PDE inhibitor), rolipram (cGMP-insensitive cAMP PDE inhibitor), and the 0.1% dimethyl sulfoxide (DMSO) vehicle control, which decreased the Ppa by 6 +/- 3, 4 +/- 3, and 0%, respectively. In the trequinsin and indolidan groups, the subsequent ANG II pressor responses and HPRs were significantly (P = 0.01) decreased when compared with the zaprinast, rolipram, and DMSO groups. During normoxia, none of the PDE inhibitor (0.3-30 microM) had an effect on the baseline Ppa. These results suggest that cAMP hydrolysis by the cGMP-inhibitable cAMP PDE play a significant role in pulmonary vascular tone regulation.
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Delporte, C., P. Poloczek, and J. Winand. "Role of phosphodiesterase II in cross talk between cGMP and cAMP in human neuroblastoma NB-OK-1 cells." American Journal of Physiology-Cell Physiology 270, no. 1 (January 1, 1996): C286—C292. http://dx.doi.org/10.1152/ajpcell.1996.270.1.c286.
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Cyclic nucleotides levels and cyclic nucleotide phosphodiesterase (PDE) activities were measured in human neuroblastoma NB-OK-1 cells possessing atrial natriuretic peptide (ANP) receptors of the A type and pituitary adenylate cyclase activating polypeptide (PACAP)-preferring receptors. Adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) degradation were interrelated since the increase in cGMP, induced by ANP-(99-126), stimulated the hydrolysis of cAMP by PDE isoenzyme II. In intact NB-OK-1 cells, the levels of cAMP and cGMP attained in the presence of, respectively, 1 nM PACAP-(1-27) and 10 nM ANP-(99-126), and in the absence or presence of PDE inhibitors, strongly suggested that cAMP hydrolysis was mainly achieved by isoenzyme IV, and to a lesser extent by isoenzymes I, II, and III, while cGMP was degraded by isoenzymes I, II, III, and V. More than one-half of total cAMP- and cGMP-hydrolyzing activities was present in the membrane-bound fraction. Cyclic nucleotide PDE activities separated by anion-exchange chromatography showed that isoenzymes III and IV were mainly present in the membrane fraction, while isoenzymes I, II, and V were in the cytosolic fraction.
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Ignarro, L. J., R. E. Byrns, G. M. Buga, and K. S. Wood. "Mechanisms of endothelium-dependent vascular smooth muscle relaxation elicited by bradykinin and VIP." American Journal of Physiology-Heart and Circulatory Physiology 253, no. 5 (November 1, 1987): H1074—H1082. http://dx.doi.org/10.1152/ajpheart.1987.253.5.h1074.
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The objective of this study was to elucidate the mechanisms by which bradykinin and vasoactive intestinal polypeptide (VIP) relax bovine intrapulmonary artery and bradykinin, but not VIP, relaxes intrapulmonary vein. Bradykinin and VIP elicited entirely endothelium-dependent relaxation of phenylephrine-precontracted arterial rings, and this was associated with arterial accumulation of both guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP). Bradykinin, but not VIP, relaxed precontracted venous rings and increased cGMP, but not cAMP levels, by endothelium-dependent mechanisms. Neither arteries nor veins relaxed in response to substance P, thrombin, bombesin, arginine vasopressin, or angiotensin II. Methylene blue or indomethacin each partially antagonized, whereas both, when together, abolished arterial relaxant responses to bradykinin and VIP. Methylene blue or indomethacin, respectively, abolished arterial cGMP or cAMP accumulation elicited by bradykinin and VIP. Venous relaxation and cGMP accumulation elicited by bradykinin was abolished by methylene blue but was unaltered by indomethacin. Thus bradykinin and VIP relaxed bovine intrapulmonary artery by endothelium-dependent mechanisms involving the actions of cGMP and cAMP whose formation may be stimulated by endothelium-derived relaxing factor and prostacyclin, respectively. In contrast, bradykinin relaxed intrapulmonary vein by endothelium-dependent mechanisms involving only cGMP.
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Witwicka, Hanna, Marcin Kobiałka, and Wojciech A. Gorczyca. "Hydrolysis of cyclic GMP in rat peritoneal macrophages." Acta Biochimica Polonica 49, no. 4 (December 31, 2002): 891–97. http://dx.doi.org/10.18388/abp.2002_3748.
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Intact rat peritoneal macrophages (rPM) treated with 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of phosphodiesterases (PDEs), accumulated more cGMP than untreated cells. A PDE activity toward [(3)H]cGMP was detected in the soluble and particulate fractions of rPM. The hydrolysis of cGMP was Ca(2+)/calmodulin-independent but increased in the presence of cGMP excess. Similar results were obtained when [(3)H]cAMP was used as a substrate. The hydrolytic activity towards both nucleotides was inhibited in the presence of IBMX. Therefore, the PDEs of families 2, 5, 10 and 11 are potential candidates for cGMP hydrolysis in the rPM. They may not only regulate the cGMP level in a feedback-controlled way but also link cGMP-dependent pathways with those regulated by cAMP.