scholarly journals A 3′,5′ Cyclic AMP (cAMP) Phosphodiesterase Modulates cAMP Levels and Optimizes Competence in Haemophilus influenzae Rd

1998 ◽  
Vol 180 (17) ◽  
pp. 4401-4405 ◽  
Author(s):  
Leah P. Macfadyen ◽  
Caixia Ma ◽  
Rosemary J. Redfield
Keyword(s):  
Cyclic Amp ◽  
Haemophilus Influenzae ◽  
Competence Development ◽  
Intracellular Camp ◽  
Camp Phosphodiesterase ◽  
E Coli ◽  
Sugar Fermentation ◽  
Endogenous Production ◽  
Camp Levels ◽  
Dependent Processes

ABSTRACT Changes in intracellular 3′,5′ cyclic AMP (cAMP) concentration regulate the development of natural competence inHaemophilus influenzae. In Escherichia coli, cAMP levels are modulated by a cAMP phosphodiesterase encoded by the cpdA gene. We have used several approaches to demonstrate that the homologous icc gene of H. influenzae encodes a functional cAMP phosphodiesterase and that this gene limits intracellular cAMP and thereby influences competence and other cAMP-dependent processes. In E. coli, expression of cloned icc reduced both cAMP-dependent sugar fermentation and β-galactosidase expression, as has been shown forcpdA. In H. influenzae, an icc null mutation increased cAMP-dependent sugar fermentation and competence development in strains where these processes are limited by mutations reducing cAMP synthesis. When endogenous production of cAMP was eliminated by a cya mutation, an icc strain was 10,000-fold more sensitive to exogenous cAMP than anicc + strain. The icc strain showed moderately elevated competence under noninducing conditions, as expected, but had subnormal competence increases at onset of stationary phase in rich medium, and on transfer to a nutrient-limited medium, suggesting that excessive cAMP may interfere with induction. Consistent with this finding, a cya strain cultured in 1 mM cAMP failed to develop maximal competence on transfer to inducing conditions. Thus, by limiting cAMP levels, the H. influenzae cAMP phosphodiesterase may coordinate its responses to nutritional stress, ensuring optimal competence development.

scholarly journals Cyclic AMP enhances the sexual agglutinability of Chlamydomonas flagella.

1989 ◽  
Vol 109 (1) ◽  
pp. 247-252 ◽  
Author(s):  
U W Goodenough
Keyword(s):  
Cell Wall ◽  
Cyclic Amp ◽  
Mating Type ◽  
Feedback System ◽  
Intracellular Camp ◽  
Camp Generation ◽  
Sexual Agglutinability ◽  
Single Mating ◽  
Wall Loss ◽  
Camp Levels

Sexual adhesion between Chlamydomonas reinhardtii gametes elicits a rise in intracellular cAMP levels, and exogenous elevation of intracellular cAMP levels in gametes of a single mating type induces such mating responses as cell wall loss, flagellar tip activation, and mating structure activation (Pasquale, S. M., and U. W. Goodenough. 1987. J. Cell Biol. 105:2279-2292). Here evidence is presented that sexual adhesion mobilizes agglutinin to the flagellar surface, and that this mobilization can be induced by exogenous presentation of cAMP to gametes of a single mating type. It is proposed that Chlamydomonas adhesion entails a positive feedback system--initial contacts stimulate the presentation of additional agglutinin--and that this feedback is mediated by adhesion-induced cAMP generation.

scholarly journals Small-molecule allosteric activators of PDE4 long form cyclic AMP phosphodiesterases

2019 ◽  
Vol 116 (27) ◽  
pp. 13320-13329 ◽  
Author(s):  
Faisa Omar ◽  
Jane E. Findlay ◽  
Gemma Carfray ◽  
Robert W. Allcock ◽  
Zhong Jiang ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Small Molecule ◽  
Protein Complexes ◽  
Cyst Formation ◽  
Camp Signaling ◽  
Intracellular Camp ◽  
Camp Phosphodiesterase ◽  
Cellular Processes ◽  
Small Molecule Compound ◽  
Autosomal Dominant Polycystic Kidney

Cyclic AMP (cAMP) phosphodiesterase-4 (PDE4) enzymes degrade cAMP and underpin the compartmentalization of cAMP signaling through their targeting to particular protein complexes and intracellular locales. We describe the discovery and characterization of a small-molecule compound that allosterically activates PDE4 long isoforms. This PDE4-specific activator displays reversible, noncompetitive kinetics of activation (increased Vmax with unchanged Km), phenocopies the ability of protein kinase A (PKA) to activate PDE4 long isoforms endogenously, and requires a dimeric enzyme assembly, as adopted by long, but not by short (monomeric), PDE4 isoforms. Abnormally elevated levels of cAMP provide a critical driver of the underpinning molecular pathology of autosomal dominant polycystic kidney disease (ADPKD) by promoting cyst formation that, ultimately, culminates in renal failure. Using both animal and human cell models of ADPKD, including ADPKD patient-derived primary cell cultures, we demonstrate that treatment with the prototypical PDE4 activator compound lowers intracellular cAMP levels, restrains cAMP-mediated signaling events, and profoundly inhibits cyst formation. PDE4 activator compounds thus have potential as therapeutics for treating disease driven by elevated cAMP signaling as well as providing a tool for evaluating the action of long PDE4 isoforms in regulating cAMP-mediated cellular processes.

scholarly journals Cyclic AMP Controls mTOR through Regulation of the Dynamic Interaction between Rheb and Phosphodiesterase 4D

2010 ◽  
Vol 30 (22) ◽  
pp. 5406-5420 ◽  
Author(s):  
Hyun Wook Kim ◽  
Sang Hoon Ha ◽  
Mi Nam Lee ◽  
Elaine Huston ◽  
Do-Hyung Kim ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Mammalian Target Of Rapamycin ◽  
Dynamic Interaction ◽  
Negative Regulator ◽  
Camp Phosphodiesterase ◽  
Extracellular Stimuli ◽  
Phosphodiesterase 4D ◽  
Signaling Components ◽  
Camp Levels ◽  
Regulatory Event

ABSTRACT The mammalian target of rapamycin complex 1 (mTORC1) is a molecular hub that regulates protein synthesis in response to a number of extracellular stimuli. Cyclic AMP (cAMP) is considered to be an important second messenger that controls mTOR; however, the signaling components of this pathway have not yet been elucidated. Here, we identify cAMP phosphodiesterase 4D (PDE4D) as a binding partner of Rheb that acts as a cAMP-specific negative regulator of mTORC1. Under basal conditions, PDE4D binds Rheb in a noncatalytic manner that does not require its cAMP-hydrolyzing activity and thereby inhibits the ability of Rheb to activate mTORC1. However, elevated cAMP levels disrupt the interaction of PDE4D with Rheb and increase the interaction between Rheb and mTOR. This enhanced Rheb-mTOR interaction induces the activation of mTORC1 and cap-dependent translation, a cellular function of mTORC1. Taken together, our results suggest a novel regulatory mechanism for mTORC1 in which the cAMP-determined dynamic interaction between Rheb and PDE4D provides a key, unique regulatory event. We also propose a new role for PDE4 as a molecular transducer for cAMP signaling.

scholarly journals Initiation of meiosis and sporulation in Saccharomyces cerevisiae does not require a decrease in cyclic AMP.

1987 ◽  
Vol 7 (6) ◽  
pp. 2141-2147 ◽  
Author(s):  
Z Olempska-Beer ◽  
E Freese
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Carbon Source ◽  
Cyclic Amp ◽  
Phosphodiesterase Inhibitor ◽  
Intracellular Camp ◽  
Glucose Medium ◽  
Camp Concentration ◽  
Ishikawa Cell ◽  
Camp Phosphodiesterase ◽  
Low Level

Meiosis and sporulation of Saccharomyces cerevisiae are initiated in a guanine auxotroph by guanine deprivation (E. Bautz Freese, Z. Olempska-Beer, A. Hartig, and E. Freese, Dev. Biol. 102:438-451, 1984). We used this condition to examine a hypothesis (K. Matsumoto, I. Uno, and T. Ishikawa, Cell 32:417-423, 1983) that initiation of meiosis requires a low level of cAMP. We found that, after guanine deprivation, the intracellular concentration of cAMP transiently decreased not more than 20% and not at all if the cAMP phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) was added to the medium. Under these conditions, at least 76% of the cells sporulated in the absence of IBMX, and almost 100% sporulated in its presence. The sporulating cells continually excreted cAMP and utilized the gluconeogenic carbon source. The cells failed to sporulate efficiently and to form four-spored asci if simultaneously deprived of guanine and carbon. After guanine deprivation in glucose medium, sporulation remained suppressed and intracellular cAMP was unchanged. We conclude that, under conditions of guanine starvation, cAMP deficiency is not required for initiation of meiosis and sporulation, cAMP is produced in excess and excreted to the medium, the cells sporulate better if the cAMP concentration is increased by addition of IBMX, the cells require a gluconeogenic carbon source for complete and efficient sporulation, and suppression of sporulation by glucose is not mediated by cAMP.

scholarly journals Adenosine 3':5'-monophosphate content and actions in the division cycle of synchronized HeLa cells.

1976 ◽  
Vol 71 (2) ◽  
pp. 515-534 ◽  
Author(s):  
C E Zeilig ◽  
R A Johnson ◽  
E W Sutherland ◽  
D L Friedman
Keyword(s):  
Cell Cycle ◽  
Cyclic Amp ◽  
Hela Cells ◽  
S Phase ◽  
Intracellular Camp ◽  
Specific Effects ◽  
Low Concentrations ◽  
High Concentrations ◽  
Camp Levels ◽  
Stimulation Of

The involvement of adenosine 3':5'-monophosphate (cAMP) in the regulation of the cell cycle was studied by determining intracellular fluctuations in cAMP levels in synchronized HeLa cells and by testing the effects of experimentally altered levels on cell cycle traverse. Cyclic AMP levels were lowest during mitosis and were highest during late G-1 or early S phase. These findings were supported by results obtained when cells were accumulated at these points with Colcemid or high levels of thymidine. Additional fluctuations in cAMP levels were observed during S phase. Two specific effects of cAMP on cell cycle traverse were found. Elevation of cAMP levels in S phase or G-2 caused arrest of cells in G-2 for as long as 10 h and lengthened M. However, once cells reached metaphase, elevation of cAMP accelerated the completion of mitosis. Stimulation of mitosis was also observed after addition of CaCl2. The specificity of the effects of cAMP was verified by demonstrating that: (a) intracellular cAMP was increased after exposure to methylisobutylxanthine (MIX) before any observed effects on cycle traverse; (b) submaximal concentrations of MIX potentiated the effects of isoproterenol; and (c) effects of MIX and isoproterenol were mimicked by 8-Br-cAMP. MIX at high concentrations inhibited G-1 traverse, but this effect did not appear to be mediated by cAMP. Isoproterenol slightly stimulated G-1 traverse and partially prevented the MIX-induced delay. Moreover, low concentrations of 8-Br-cAMP (0.10-100 muM) stimulated G-1 traverse, whereas high concentrations (1 mM) inhibited. Both of these effects were also observed with the control, Br-5'-AMP, at 10-fold lower concentrations.

Initiation of meiosis and sporulation in Saccharomyces cerevisiae does not require a decrease in cyclic AMP

1987 ◽  
Vol 7 (6) ◽  
pp. 2141-2147
Author(s):  
Z Olempska-Beer ◽  
E Freese
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Carbon Source ◽  
Cyclic Amp ◽  
Phosphodiesterase Inhibitor ◽  
Intracellular Camp ◽  
Glucose Medium ◽  
Camp Concentration ◽  
Ishikawa Cell ◽  
Camp Phosphodiesterase ◽  
Low Level

Meiosis and sporulation of Saccharomyces cerevisiae are initiated in a guanine auxotroph by guanine deprivation (E. Bautz Freese, Z. Olempska-Beer, A. Hartig, and E. Freese, Dev. Biol. 102:438-451, 1984). We used this condition to examine a hypothesis (K. Matsumoto, I. Uno, and T. Ishikawa, Cell 32:417-423, 1983) that initiation of meiosis requires a low level of cAMP. We found that, after guanine deprivation, the intracellular concentration of cAMP transiently decreased not more than 20% and not at all if the cAMP phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) was added to the medium. Under these conditions, at least 76% of the cells sporulated in the absence of IBMX, and almost 100% sporulated in its presence. The sporulating cells continually excreted cAMP and utilized the gluconeogenic carbon source. The cells failed to sporulate efficiently and to form four-spored asci if simultaneously deprived of guanine and carbon. After guanine deprivation in glucose medium, sporulation remained suppressed and intracellular cAMP was unchanged. We conclude that, under conditions of guanine starvation, cAMP deficiency is not required for initiation of meiosis and sporulation, cAMP is produced in excess and excreted to the medium, the cells sporulate better if the cAMP concentration is increased by addition of IBMX, the cells require a gluconeogenic carbon source for complete and efficient sporulation, and suppression of sporulation by glucose is not mediated by cAMP.

Cyclic AMP-phosphodiesterase induces dedifferentiation of prespore cells in Dictyostelium discoideum slugs: evidence that cyclic AMP is the morphogenetic signal for prespore differentiation

Development ◽  
1988 ◽  
Vol 103 (3) ◽  
pp. 611-618 ◽  
Author(s):  
M. Wang ◽  
R. van Driel ◽  
P. Schaap
Keyword(s):  
Cyclic Amp ◽  
Hydrolysis Product ◽  
Camp Level ◽  
Camp Phosphodiesterase ◽  
Multicellular Development ◽  
Local Reduction ◽  
Coated Spheres ◽  
Extracellular Camp ◽  
Camp Levels ◽  
General Reduction

We investigated whether cyclic AMP is an essential extracellular stimulus for the differentiation of prespore cells in slugs of D. discoideum. A local reduction of the extracellular cAMP level inside the slug was induced by implantation of cAMP-phosphodiesterase (cAMP-PDE)-coated spheres in intact slugs. This treatment caused the disappearance of prespore antigen in the vicinity of the sphere. A general reduction of extracellular cAMP levels in slugs, induced by submerging slugs in 0.25i.u.ml-1 cAMP-PDE, reduced the proportion of prespore cells from 66% to 15%, without affecting slug morphology. The cAMP-PDE-induced dedifferentiation of prespore cells was counteracted by cAMP and was not due to the production of the hydrolysis product 5′AMP, but to the reduction of extracellular cAMP levels. We conclude that extracellular cAMP is the major morphogenetic signal for the differentiation of prespore cells in the multicellular stages of D. discoideum development and we present a working hypothesis for the generation of the prestalk/prespore pattern during multicellular development.

Cyclic AMP phosphodiesterase: a regulator of forward motility initiation during epididymal sperm maturation

1996 ◽  
Vol 74 (5) ◽  
pp. 669-674 ◽  
Author(s):  
Bijay S. Jaiswal ◽  
Gopal C. Majumder
Keyword(s):  
Cyclic Amp ◽  
Specific Inhibitor ◽  
Flagellar Motility ◽  
Epididymal Sperm ◽  
Camp Phosphodiesterase ◽  
Cyclic Amp Phosphodiesterase ◽  
Epididymal Maturation ◽  
Camp Levels ◽  
Sperm Maturity

The concentrations of cAMP, cAMP phosphodiesterase (PDE) activity, and the effect of theophylline in vitro on the forward motility (FM) of maturing goat epididymal sperm have been analyzed. cAMP levels increased slowly during transit of the cells from the caput to the proximal cauda, although they acquired a minimal degree of forward progression. The last phase of sperm transit (proximal to distal cauda) was associated with a concomitant sharp rise in the level of both c AMP as well as flagellar motility. PDE activity progressively decreased (approximately threefold) during epididymal maturation, being minimal in mature cauda sperm. Theophylline (30 mM), a specific inhibitor of PDE, markedly activated (10-fold or greater) motility of the sperm derived from proximal-corpus, mid-corpus, distal-corpus, and proximal-cauda epididymides. FM of the native mature caudal sperm was similar to that of the theophylline-treated proximal-cauda sperm. The terminal stage of sperm maturity (proximal to distal cauda) was associated with a markedly reduced level of theophylline-dependent motility activation (approximately 50%). The data are consistent with the view that PDE plays an important role in the initiation of motility during epididymal sperm maturation.Key words: epididymal sperm, cyclic AMP, cyclic AMP phosphodiesterase, flagellar motility, theophylline

scholarly journals Cyclic AMP-Independent Control of Twitching Motility in Pseudomonas aeruginosa

2017 ◽  
Vol 199 (16) ◽  
Author(s):  
Ryan N. C. Buensuceso ◽  
Martin Daniel-Ivad ◽  
Sara L. N. Kilmury ◽  
Tiffany L. Leighton ◽  
Hanjeong Harvey ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Cyclic Amp ◽  
Response Regulator ◽  
Opportunistic Pathogen ◽  
Regulatory Elements ◽  
Twitching Motility ◽  
Camp Phosphodiesterase ◽  
Content Type ◽  
Polar Localization ◽  
Camp Levels

ABSTRACT FimV is a Pseudomonas aeruginosa inner membrane hub protein that modulates levels of the second messenger, cyclic AMP (cAMP), through the activation of adenylate cyclase CyaB. Although type IVa pilus (T4aP)-dependent twitching motility is modulated by cAMP levels, mutants lacking FimV are twitching impaired, even when exogenous cAMP is provided. Here we further define FimV's cAMP-dependent and -independent regulation of twitching. We confirmed that the response regulator of the T4aP-associated Chp chemotaxis system, PilG, requires both FimV and the CyaB regulator, FimL, to activate CyaB. However, in cAMP-replete backgrounds—lacking the cAMP phosphodiesterase CpdA or the CheY-like protein PilH or expressing constitutively active CyaB—pilG and fimV mutants failed to twitch. Both cytoplasmic and periplasmic domains of FimV were important for its cAMP-dependent and -independent roles, while its septal peptidoglycan-targeting LysM motif was required only for twitching motility. Polar localization of the sensor kinase PilS, a key regulator of transcription of the major pilin, was FimV dependent. However, unlike its homologues in other species that localize flagellar system components, FimV was not required for swimming motility. These data provide further evidence to support FimV's role as a key hub protein that coordinates the polar localization and function of multiple structural and regulatory proteins involved in P. aeruginosa twitching motility. IMPORTANCE Pseudomonas aeruginosa is a serious opportunistic pathogen. Type IVa pili (T4aP) are important for its virulence, because they mediate dissemination and invasion via twitching motility and are involved in surface sensing, which modulates pathogenicity via changes in cAMP levels. Here we show that the hub protein FimV and the response regulator of the Chp system, PilG, regulate twitching independently of their roles in the modulation of cAMP synthesis. These functions do not require the putative scaffold protein FimL, proposed to link PilG with FimV. PilG may regulate asymmetric functioning of the T4aP system to allow for directional movement, while FimV appears to localize both structural and regulatory elements—including the PilSR two-component system—to cell poles for optimal function.

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