scholarly journals Role of cAMP Signaling in the Survival and Infectivity of the Protozoan Parasite, Leishmania donovani

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Arunima Biswas ◽  
Arijit Bhattacharya ◽  
Pijush K. Das
Keyword(s):  
Leishmania Donovani ◽  
Protozoan Parasite ◽  
Camp Level ◽  
Camp Signaling ◽  
Regulatory Subunit ◽  
Developmentally Regulated ◽  
Camp Phosphodiesterase ◽  
Environmental Trigger ◽  
Dependent Protein ◽  
Camp Metabolism

Leishmania donovani, while invading macrophages, encounters striking shift in temperature and pH (from 22°C and pH 7.2 to 37°C and pH 5.5), which act as the key environmental trigger for differentiation, and increases cAMP level and cAMP-mediated responses. For comprehensive understanding of cAMP signaling, we studied the enzymes related to cAMP metabolism. A stage-specific and developmentally regulated isoform of receptor adenylate cyclase (LdRACA) showed to regulate differentiation-coupled induction of cAMP. The soluble acidocalcisomal pyrophosphatase, Ldvsp1, was the major isoform regulating cAMP level in association with LdRACA. A differentially expressed soluble cytosolic cAMP phosphodiesterase (LdPDEA) might be related to infection establishment by shifting trypanothione pool utilization bias toward antioxidant defense. We identified and cloned a functional cAMP-binding effector molecule from L. donovani (a regulatory subunit of cAMP-dependent protein kinase, LdPKAR) that may modulate metacyclogenesis through induction of autophagy. This study reveals the significance of cAMP signaling in parasite survival and infectivity.

A cAMP-phosphodiesterase controls PKA-dependent differentiation

Development ◽  
1998 ◽  
Vol 125 (4) ◽  
pp. 691-699 ◽  
Author(s):  
G. Shaulsky ◽  
D. Fuller ◽  
W.F. Loomis
Keyword(s):  
Terminal Differentiation ◽  
Regulatory Subunit ◽  
Check Point ◽  
Two Component System ◽  
Dependent Protein Kinase ◽  
Camp Phosphodiesterase ◽  
Component System ◽  
Two Component ◽  
Dependent Protein ◽  
Higher Eukaryotes

A cAMP-specific phosphodiesterase was found that is stimulated by binding to the regulatory subunit of cAMP-dependent protein kinase, PKA-R, from either Dictyostelium or mammals. The phosphodiesterase is encoded by the regA gene of Dictyostelium, which was recovered in a mutant screen for strains that sporulate in the absence of signals from prestalk cells. The sequence of RegA predicts that it will function as a member of a two-component system. Genetic analyses indicate that inhibition of the phosphodiesterase results in an increase in the activity of PKA, which acts at a check point for terminal differentiation. Conserved components known to affect memory, learning and differentiation in flies and vertebrates suggest that a similar circuitry functions in higher eukaryotes.

Antiplatelet Effect Of A New Compound, Imidazo[1,2-a]- Thienopyrimidin-2-One : A Cyclic AMP Mediated Phenomenon

1981 ◽  
Author(s):  
S Ashida ◽  
K Sakuma ◽  
Y Abiko
Keyword(s):  
Platelet Aggregation ◽  
Membrane Fraction ◽  
Close Correlation ◽  
Inhibitory Effect ◽  
Camp Level ◽  
Camp Phosphodiesterase ◽  
Pde Inhibitors ◽  
Camp Metabolism ◽  
Oral Doses

The effect of a new compound, 1,2,3,5,6,7,8,9-Octahydro- [1]benzothieno[2,3-d]imidazo[1,2-a]pyrimidin-2-one hydrochloride (DH-6471), on cAMP metabolism and aggregation of platelets was studied. In vitro. DH-6471 inhibited platelet aggregation (both the 1st and 2nd phases) induced by ADP, collagen, thrombin, arachidonic acid and PGG2-TXA2 mixture in PRP from various animal species including human at concentrations (IC50) ranging from 0.07 to 8 μH. It inhibited ADP- and collagen-induced platelet aggregation ex vivg in rats following oral doses as low as 0.3- 1 mg/kg.The compound was found to be a highly selective inhibitor of platelet low Km cAMP phosphodiesterase (Ki=0.025 μM), when tested with enzyme fractions separated by DEAE-cellu-lose chromatography. It did not significantly affect basal or PGE1(0.1-1 μM)-stimulated cAMP level of platelets at a concentration of 1 μM where platelet aggregation and the low Km PDE were markedly inhibited. However, both basal and PGE1-stimulated accumulations of cAMP in the platelet membrane fraction were increased by DH-6471 at 1 μM when the isolated membrane fraction was incubated with ATP-Mg2+.Studies with several PDE inhibitors including papaverine, dipyridamole and DH-6471-related compounds showed a close correlation between their ability to inhibit the low Km PDE or to increase cAMP accumulation in the membrane fraction and their inhibitory effect on platelet aggregation. On the other hand, their potency to inhibit high Km cAMP-PDE(cGMP-PDE) and to increase cAMP level in whole platelets was poorly correlated to their inhibitory activity in platelet aggregation.These results suggest that some small but local changes in platelet cAMP may be involved in the regulation of platelet aggregation, particularly primary aggregation.

scholarly journals Role of PKA in the Timing of Developmental Events in Dictyostelium Cells

1998 ◽  
Vol 62 (3) ◽  
pp. 684-694 ◽  
Author(s):  
William F. Loomis
Keyword(s):  
Transcriptional Activation ◽  
Signal Transduction Pathway ◽  
Genetic Alterations ◽  
Catalytic Subunit ◽  
Regulatory Subunit ◽  
Relative Timing ◽  
Gene Encoding ◽  
Camp Phosphodiesterase ◽  
In The Wild ◽  
Dependent Protein

SUMMARY The cyclic AMP (cAMP)-dependent protein kinase, PKA, is dispensable for growth of Dictyostelium cells but plays a variety of crucial roles in development. The catalytic subunit of PKA is inhibited when associated with its regulatory subunit but is activated when cAMP binds to the regulatory subunit. Deletion of pkaR or overexpression of the gene encoding the catalytic subunit, pkaC, results in constitutive activity. Development is independent of cAMP in strains carrying these genetic alterations and proceeds rapidly to the formation of both spores and stalk cells. However, morphogenesis is aberrant in these mutants. In the wild type, PKA activity functions in a circuit that can spontaneously generate pulses of cAMP necessary for long-range aggregation. It is also essential for transcriptional activation of both prespore and prestalk genes during the slug stage. During culmination, PKA functions in both prespore and prestalk cells to regulate the relative timing of terminal differentiation. A positive feedback loop results in the rapid release of a signal peptide, SDF-2, when prestalk cells are exposed to low levels of SDF-2. The signal transduction pathway that mediates the response to SDF-2 in both prestalk and prespore cells involves the two-component system of DhkA and RegA. When the cAMP phosphodiesterase RegA is inhibited, cAMP accumulates and activates PKA, leading to vacuolation of stalk cells and encapsulation of spores. These studies indicate that multiple inputs regulate PKA activity to control the relative timing of differentiations in Dictyostelium.

Natural and synthetic indirubins as potent and selective inhibitors of the protozoan parasite Leishmania donovani

Planta Medica ◽  
2007 ◽  
Vol 73 (09) ◽  
Author(s):  
E Xingi ◽  
D Smirlis ◽  
S Bisti ◽  
V Myrianthopoulos ◽  
P Magiatis ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Protozoan Parasite ◽  
Selective Inhibitors ◽  
Parasite Leishmania ◽  
Natural And Synthetic
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