Effect of Δ9 tetrahydrocannabinol on cyclic nucleotides in synchronously dividing Tetrahymena

1981 ◽  
Vol 59 (7) ◽  
pp. 489-493 ◽  
Author(s):  
Selma Zimmerman ◽  
Arthur M. Zimmerman ◽  
Helen Laurence
Keyword(s):  
Cell Cycle ◽  
Nous Avons ◽  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
Significant Variation ◽  
Experimental Treatment ◽  
Twofold Increase ◽  
Synchronized Cells ◽  
Free Running ◽  
Camp And Cgmp

Cyclic nucleotide levels were determined in division-synchronized Tetrahymena and the effect of Δ9-tetrahydrocannabinol (THC) on the cyclic nucleotide levels was studied. In non-drug-treated division-synchronized cells, there was no statistically significant variation in the level of cAMP and cGMP during the G2 period, preceding the first division. During the free running cell cycle (the interval of time between the first and second synchronous division) the twofold increase in the level of cAMP was statistically significant; however the variation in the level of cGMP was not statistically significant.THC caused a lowering of cAMP and cGMP levels throughout the 4-h experimental treatment. The suppression of cAMP and cGMP levels altered the cyclic nucleotide pattern of the cell cycle. The cAMP pattern was changed particularly in the G2 period preceding the first synchronous division, and immediately after division during the free running cell cycle. THC treatment caused division delays of approximately 8–15 min in the onset of the first and second synchronous division. However, the duration of the free running cell cycle (110–120 min) was unchanged. The suppression of cyclic nucleotide levels resulting from THC treatment is discussed in relation to delays in the division schedule.Nous avons déterminé le taux des nucléotides cycliques chez Tetrahymena se divisant de façon synchrone et nous avons étudié l'effet du Δ9-tétrahydrocannabinol (THC) sur le taux de ces nucléotides cycliques. Dans les cellules non traitées, se divisant de façon synchrone, il n'existe aucune variation statistiquement significative dans les teneurs du cAMP et du cGMP durant la période G2 précédant la première division. Durant le cycle cellulaire sans division (l'intervalle de temps entre la première et la seconde division synchrone), la teneur du cAMP augmente de deux fois, une augmentation statistiquement significative; cependant, la variation du taux du cGMP n'est pas statistiquement significative.

Reduction of cAMP and cGMP inhibitory effects in human platelets by MRP4-mediated transport

2012 ◽  
Vol 108 (11) ◽  
pp. 955-962 ◽  
Author(s):  
Alessandra Borgognone ◽  
Fabio Pulcinelli
Keyword(s):  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
Thrombus Formation ◽  
Physiological Mechanism ◽  
Human Platelets ◽  
Inhibitory Effects ◽  
Dense Granules ◽  
Dependent Inhibition ◽  
Novel Target ◽  
Camp And Cgmp

SummaryCyclic nucleotide-dependent inhibition of platelets represents the most important physiological way to limit thrombus formation. cAMP and cGMP increase in platelets as a consequence of prostacyclin and nitric oxide production by endothelial cells and act through PKA and PKG, respectively. The cytosolic concentration of cyclic nucleotides in platelets is regulated by AC- and GC-dependent synthesis and PDE-dependent degradation. In some cells cyclic nucleotides are eliminated also through MRP4/5/8-dependent efflux. As only MRP4 is expressed in platelets, at high levels in dense granules, we determined its role in the elimination of cyclic nucleotides from platelet cytosol. We studied the effects of MRP4 inhibition on cAMP/cGMP effects in platelets. Cyclic nucleotide inhibitory effects triggered by cAMP and cGMP-elevating agents on platelet aggregation are strongly enhanced by MRP4 inhibition and so is cyclic nucleotide-dependent phosphorylation of the common substrate VASP. MRP4 inhibition decreases cAMP concentration in platelet granules and both cAMP and cGMP compete with an established substrate of MRP4 (fluo-cAMP) for entrance in granules. Here we provide the first evidence of the transport of cyclic nucleotides mediated by MRP4 as part of their physiological mechanism of elimination in human platelets, which might represent a novel target to increase cyclic nucleotide-dependent inhibition.

Cyclic Nucleotides Signaling and Phosphodiesterase Inhibition: Defying Alzheimer’s Disease

2020 ◽  
Vol 21 (13) ◽  
pp. 1371-1384 ◽  
Author(s):  
Vivek K. Sharma ◽  
Thakur G. Singh ◽  
Shareen Singh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
Phosphodiesterase Inhibitors ◽  
Physiological Status ◽  
Altered Expression ◽  
Brain Functions ◽  
Nucleotide Signaling ◽  
Camp And Cgmp

Defects in brain functions associated with aging and neurodegenerative diseases benefit insignificantly from existing options, suggesting that there is a lack of understanding of pathological mechanisms. Alzheimer’s disease (AD) is such a nearly untreatable, allied to age neurological deterioration for which only the symptomatic cure is available and the agents able to mould progression of the disease, is still far away. The altered expression of phosphodiesterases (PDE) and deregulated cyclic nucleotide signaling in AD has provoked a new thought of targeting cyclic nucleotide signaling in AD. Targeting cyclic nucleotides as an intracellular messenger seems to be a viable approach for certain biological processes in the brain and controlling substantial. Whereas, the synthesis, execution, and/or degradation of cyclic nucleotides has been closely linked to cognitive deficits. In relation to cognition, the cyclic nucleotides (cAMP and cGMP) have an imperative execution in different phases of memory, including gene transcription, neurogenesis, neuronal circuitry, synaptic plasticity and neuronal survival, etc. AD is witnessed by impairments of these basic processes underlying cognition, suggesting a crucial role of cAMP/cGMP signaling in AD populations. Phosphodiesterase inhibitors are the exclusive set of enzymes to facilitate hydrolysis and degradation of cAMP and cGMP thereby, maintains their optimum levels initiating it as an interesting target to explore. The present work reviews a neuroprotective and substantial influence of PDE inhibition on physiological status, pathological progression and neurobiological markers of AD in consonance with the intensities of cAMP and cGMP.

CHANGES IN CYCLIC NUCLEOTIDES OF RAT THYROID BY CHRONIC ADMINISTRATION OF LATS AND TSH

1978 ◽  
Vol 88 (4) ◽  
pp. 713-720 ◽  
Author(s):  
Yukio Ochi ◽  
Shiro Hosoda ◽  
Takashi Hachiya ◽  
Yoshihiro Kajita ◽  
Manabu Yoshimura ◽  
...  
Keyword(s):  
Atpase Activity ◽  
Enzymatic Activity ◽  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
Chronic Administration ◽  
Nucleotidase Activity ◽  
Continuous Administration ◽  
Wet Weight ◽  
Rat Thyroid ◽  
Camp And Cgmp

ABSTRACT The effects of LATS and TSH on the cyclic nucleotide content and enzymatic activity in rat thyroid was observed during the continuous administration of LATS or TSH for 6 days. Serum T4 and T3 levels were increased significantly compared with the saline controls. The cyclic nucleotide (cAMP and cGMP) levels and enzyme activities per wet weight of tissue were determined. The thyroid weight in both the LATS and TSH groups increased approximately two-fold, but cAMP and cGMP content per wet weight did not significantly change. Neither cyclic nucleotide showed any significant change in plasma. The cAMP-PDE activity in the thyroid significantly increased in both the LATS and TSH groups, but the cGMP-PDE activity was unchanged. Neither was cyclic nucleotide-PDE activity changed in the plasma. The ATPase activity in the thyroid increased markedly in both the LATS and TSH groups, while 5′-nucleotidase activity did not change. These data suggest that LATS and TSH appear to have a stimulatory effect on the metabolism of cAMP, but do not affect the metabolism of cGMP.

Biochemical changes in progressive muscular dystrophy. XII. Cyclic nucleotides in lymphoid and nonlymphoid organs of dystrophic mice

1986 ◽  
Vol 64 (12) ◽  
pp. 1339-1348 ◽  
Author(s):  
Manohar Thakur ◽  
Mikael Sebag ◽  
Uma Srivastava
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Cyclic Nucleotides ◽  
Significant Variation ◽  
Lymphoid Organs ◽  
Immune Responsiveness ◽  
Sharp Decline ◽  
Progressive Muscular Dystrophy ◽  
Camp And Cgmp ◽  
Dystrophic Mice

Concentrations of cAMP and cGMP were measured (per milligram DNA) in the lymphoid (thymus, spleen) and nonlymphoid organs (liver, brain, kidney, lungs, heart, pancreas, skeletal muscle, lens) of normal (+/+) and dystrophic (dy/dy) 129 ReJ mice aged 30, 60, and 90 days. The cAMP concentrations in the thymus did not reveal any significant differences at 30 and 60 days of dystrophy, but were considerably higher (2-fold) at 90 days. cGMP concentrations were decreased in the thymus at 30 days (0.20-fold) and markedly elevated at 60 (2-fold) and 90 days (3-fold) of the disease. The [cAMP]/[cGMP] ratio was increased (1.30-fold) at 30 days of dystrophy, and this was followed by a sharp decline at 60 days (2-fold), with a lesser decrease at 90 days (0.34-fold). In the spleen, the cAMP concentrations were augmented significantly in all stages of dystrophy (1.5- to 2.6-fold). cGMP (per milligram DNA) did not show any significant variation at 30 and 60 days of the disease but was increased (3-fold) at 90 days. The [cAMP]/[cGMP] ratio, which was enhanced in the spleen at 30 (2-fold) and 60 days (1.5-fold), demonstrated no change at 90 days of dystrophy. These results indicated significant differences in the concentration of cyclic nucleotides and their ratios in the thymus and spleen of 129 ReJ dy/dy mice. The modifications were not limited to lymphoid organs alone, having been noted in the nonlymphoid organs as well. These changes could, in turn, influence immune responsiveness and could cause immunodepression in dystrophic mice.

Binding of cyclic nucleotides to phosphodiesterase 10A and 11A GAF domains does not stimulate catalytic activity

2009 ◽  
Vol 423 (3) ◽  
pp. 401-409 ◽  
Author(s):  
Karina Matthiesen ◽  
Jacob Nielsen
Keyword(s):  
Catalytic Activity ◽  
Ligand Binding ◽  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
Terminal Part ◽  
Indirect Assessment ◽  
High Affinity ◽  
Catalytic Sites ◽  
Phosphodiesterase 10A ◽  
Camp And Cgmp

To date eleven human PDE (3′,5′-cyclic nucleotide phosphodiesterase) families have been identified. Of these, five families contain non-catalytic tandem GAF (cGMP-specific and -stimulated phosphodiesterases, Anabaenaadenylate cyclases and Escherichia coliFhlA) domains, GAFa and GAFb, in the N-terminal part of the enzyme. For PDE2A, PDE5A and PDE6 the GAF domains have been shown to bind cGMP with high affinity. For PDE2A and PDE5A this ligand binding has been shown to stimulate the catalytic activity of the enzyme. PDE10A and PDE11A are the two most recently described PDEs and it has been suggested that their GAF domains bind to cAMP and cGMP respectively. We have developed a scintillation proximity-based assay to directly measure cyclic nucleotide binding to the PDE2A, PDE10A and PDE11A GAF domains, and in the present study we demonstrate binding of cyclic nucleotides to the PDE10A and PDE11A GAF domains. We show that these non-catalytic sites bind cAMP and cGMP respectively with much higher affinity than has previously been suggested using indirect assessment of the interaction. The GAFb domain of PDE10A binds cAMP with a Kd of 48 nM and the GAFa domain of PDE11A binds cGMP with a Kd of 110 nM. The effect of cyclic nucleotides binding to the GAF domains on the enzyme activity was investigated through the use of modified cyclic nucleotides. In contrast with other GAF domain-containing PDEs, and with what has previously been predicted, ligand binding to the GAF domains of PDE10A and PDE11A does not stimulate catalytic activity.

scholarly journals Phosphodiesterase 1 Bridges Glutamate Inputs with NO- and Dopamine-Induced Cyclic Nucleotide Signals in the Striatum

2019 ◽  
Vol 29 (12) ◽  
pp. 5022-5036 ◽  
Author(s):  
Dahdjim B Betolngar ◽  
Élia Mota ◽  
Arne Fabritius ◽  
Jacob Nielsen ◽  
Charlotte Hougaard ◽  
...  
Keyword(s):  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
Brain Slices ◽  
Long Term Potentiation ◽  
D1 Receptor ◽  
Newborn Mice ◽  
Term Potentiation ◽  
Therapeutic Value ◽  
Camp And Cgmp

Abstract The calcium-regulated phosphodiesterase 1 (PDE1) family is highly expressed in the brain, but its functional role in neurones is poorly understood. Using the selective PDE1 inhibitor Lu AF64196 and biosensors for cyclic nucleotides including a novel biosensor for cGMP, we analyzed the effect of PDE1 on cAMP and cGMP in individual neurones in brain slices from male newborn mice. Release of caged NMDA triggered a transient increase of intracellular calcium, which was associated with a decrease in cAMP and cGMP in medium spiny neurones in the striatum. Lu AF64196 alone did not increase neuronal cyclic nucleotide levels, but blocked the NMDA-induced reduction in cyclic nucleotides indicating that this was mediated by calcium-activated PDE1. Similar effects were observed in the prefrontal cortex and the hippocampus. Upon corelease of dopamine and NMDA, PDE1 was shown to down-regulate the D1-receptor mediated increase in cAMP. PDE1 inhibition increased long-term potentiation in rat ventral striatum, showing that PDE1 is implicated in the regulation of synaptic plasticity. Overall, our results show that PDE1 reduces cyclic nucleotide signaling in the context of glutamate and dopamine coincidence. This effect could have a therapeutic value for treating brain disorders related to dysfunctions in dopamine neuromodulation.

scholarly journals Platelet Resistance to the Antiaggregatory Cyclic Nucleotides in Central Obesity Involves Reduced Phosphorylation of Vasodilator-Stimulated Phosphoprotein

2007 ◽  
Vol 53 (6) ◽  
pp. 1053-1060 ◽  
Author(s):  
Isabella Russo ◽  
Paola Del Mese ◽  
Gabriella Doronzo ◽  
Alessandro De Salve ◽  
Mariantonietta Secchi ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
Central Obesity ◽  
Platelet Rich Plasma ◽  
Model Assessment ◽  
Platelet Response ◽  
Nucleotide Analogs ◽  
Assessment Index ◽  
Camp And Cgmp

Abstract Background: Impairment of platelet response to antiaggregatory agents is seen in individuals with central obesity and may play a role in the increased cardiovascular risk associated with obesity. In this study we evaluated whether this impairment involves the antiaggregatory pathways regulated by cAMP and cGMP. Methods: We obtained platelet-rich plasma from 12 obese individuals and 12 controls. We investigated the effects of the cyclic nucleotide analogs 8-pCPT-cAMP (10–500 μmol/L) and 8-pCPT-cGMP (10–500 μmol/L) on ADP-induced platelet aggregation as assessed by decreased light scattering. We assessed the activation of cAMP- and cGMP-dependent protein kinases by measuring phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) at Ser157 and Ser239. Results: The antiaggregatory effect of both cyclic nucleotide analogs was impaired in obese individuals compared to controls, with mean (SE) half-maximal inhibitory concentrations (IC50) (after 20-min incubation) of 123 (33) μmol/L vs 5 (1) μmol/L, respectively, for 8-pCPT-cAMP (P <0.01) and of 172 (43) μmol/L vs 17 (8) μmol/L, respectively, for 8-pCPT-cGMP (P <0.01). The Homeostasis Model Assessment Index of Insulin Resistance was independently correlated with cyclic nucleotide analog IC50. In obese individuals, VASP phosphorylation at Ser157 and Ser239 in response to cyclic nucleotides was significantly lower than in controls. Conclusions: In central obesity the reduced ability of cyclic nucleotides to inhibit platelet aggregation is associated with reduced activation of their specific kinases. Because cyclic nucleotides help regulate platelet antiaggregation, alteration of this ability is consistent with platelet hyperactivity in obesity.

scholarly journals Quantification of cAMP and cGMP analogs in intact cells: pitfals in enzyme immunoassays for cyclic nucleotides

2011 ◽  
Vol 11 (S1) ◽  
Author(s):  
Katharina Werner ◽  
Frank Schwede ◽  
Hans-Gottfried Genieser ◽  
Jörg Geiger ◽  
Elke Butt
Keyword(s):  
Cyclic Nucleotides ◽  
Intact Cells ◽  
Enzyme Immunoassays ◽  
Camp And Cgmp

scholarly journals CHANGES IN THE DNA SYNTHESIS PATTERN OF PARAMECIUM WITH INCREASED CLONAL AGE AND INTERFISSION TIME

1974 ◽  
Vol 61 (3) ◽  
pp. 591-598 ◽  
Author(s):  
Joan Smith-Sonneborn ◽  
Michael Klass
Keyword(s):  
Cell Cycle ◽  
Dna Synthesis ◽  
Unicellular Organism ◽  
Time Intervals ◽  
Synchronized Cells ◽  
Different Ages ◽  
Self Fertilization ◽  
Autoradiographic Analysis ◽  
S Period ◽  
First Time

The clonal age in paramecia refers to the total number of vegetative divisions a clone has undergone since its origin at autogamy (self-fertilization). As clonal age increases, the interfission time usually increases. The DNA synthesis pattern of cells of different ages was compared by autoradiographic analysis of the DNA synthesis of synchronized cells at various time intervals during the cell cycle (from one division to the next). The study showed that the G1 period (the lag in DNA synthesis post division) was constant, irrespective of interfission time or clonal age; but the duration of the DNA synthesis period increased with increased interfission time or clonal age. Therefore, we have shown for the first time that the G1 period is fixed, and the S period is increased in a eukaryotic unicellular organism as a function of interfission time and clonal age.

Absence of a correlation between cyclic nucleotide fluctuations and cell cycle progression

1981 ◽  
Vol 131 (2) ◽  
pp. 373-377 ◽  
Author(s):  
Nancy L. Oleinick ◽  
John W. Daniel ◽  
Eugene N. Brewer
Keyword(s):  
Cell Cycle ◽  
Cyclic Nucleotide ◽  
Cell Cycle Progression ◽  
Cycle Progression
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