Calmodulin and Ca2+-dependent cyclic AMP phosphodiesterase activity in Trypanosoma cruzi

Téllez-Iñón, Marı́a T.; Ulloa, Rita M.; Torruella, M; Torres, Héctor N.

doi:10.1016/0166-6851(85)90013-1

Cited by 62 publications

(30 citation statements)

References 25 publications

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“…Nonselective PDE inhibitors slightly affected PDE activities present in T. cruzi (16), T. gambiense (12), L. donovani (13), L. mexicana (20), and TbPDE2A (19). An extremely low inhibition by the selective PDE inhibitors for PDE3 (enoximone), PDE4 (rolipram, Ro 20-1724), and PDE5 has been also shown for L. mexicana PDEs (20) and TbPDE2A (19).…”

Section: Discussionmentioning

confidence: 99%

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Cloning and characterization of a cAMP-specific phosphodiesterase (TbPDE2B) from Trypanosoma brucei

Rascón

Soderling

Schaefer

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Here we report the cloning, expression, and characterization of a cAMP-specific phosphodiesterase (PDE) from Trypanosoma brucei (TbPDE2B). Using a bioinformatic approach, two different expressed sequence tag clones were identified and used to isolate the complete sequence of two identical PDE genes arranged in tandem. Each gene consists of 2,793 bases that predict a protein of 930 aa with a molecular mass of 103.2 kDa. Two GAF (for cGMP binding and stimulated PDEs, Anabaena adenylyl cyclases, and Escherichia coli FhlA) domains, similar to those contained in many signaling molecules including mammalian PDE2, PDE5, PDE6, PDE10, and PDE11, were located N-terminal to a consensus PDE catalytic domain. The catalytic domain is homologous to the catalytic domain of all 11 mammalian PDEs, the Dictyostelium discoideum RegA, and a probable PDE from Caenorhabditis elegans. It is most similar to the T. brucei PDE2A (89% identity). TbPDE2B has substrate specificity for cAMP with a K m of 2.4 M. cGMP is not hydrolyzed by TbPDE2B nor does this cyclic nucleotide modulate cAMP PDE activity. The nonselective PDE inhibitors 3-isobutyl-1-methylxanthine, papaverine and pentoxifyline are poor inhibitors of TbPDE2B. Similarly, PDE inhibitors selective for the mammalian PDE families 2, 3, 5, and 6 (erythro-9-[3-(2-hydroxynonyl)]-adenine, enoximone, zaprinast, and sildenafil) were also unable to inhibit this enzyme. However, dipyridamole was a reasonably good inhibitor of this enzyme with an IC50 of 27 M. cAMP plays key roles in cell growth and differentiation in this parasite, and PDEs are responsible for the hydrolysis of this important second messenger. Therefore, parasite PDEs, including this one, have the potential to be attractive targets for selective drug design.inhibitors ͉ GAF domain

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Section: Discussionmentioning

confidence: 99%

“…Since then, two reports (15,16) have been published on this topic in T. cruzi, with somewhat contradictory results. The first reports for cloning and expression of a PDE from T. brucei were the recent descriptions of TbPDE2A and TbPDE1 (17)(18)(19).…”

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confidence: 99%

Cloning and characterization of a cAMP-specific phosphodiesterase (TbPDE2B) from Trypanosoma brucei

Rascón

Soderling

Schaefer

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, the demonstration of differentiation-specific fluctuations in the cAMP level has resulted in an analysis of the modulation of adenylate cyclase activity as well as the metabolism of cAMP. TellezInon et al (268) have demonstrated the presence of a calmodulin-regulated cAMP-dependent phosphodiesterase. In related work with a calmodulin gel overlay procedure, the existence of stage-specific calmodulin-binding proteins in this parasite has been demonstrated (185).…”

Section: Introductionmentioning

confidence: 99%

Chagas' disease

et al. 1992

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Chagas' disease, caused by Trypanosoma cruzi, is an important cause of morbidity in many countries in Latin America. The important modes of transmission are by the bite of the reduviid bug and blood transfusion. The organism exists in three morphological forms: trypomastigotes, amastigotes, and epimastigotes. The mechanism of transformation and differentiation is currently being explored, and signal transduction pathways of the parasites may be involved in this process. Parasite adherence to and invasion of host cells is a complex process involving complement, phospholipase, penetrin, neuraminidase, and hemolysin. Two clinical forms of the disease are recognized, acute and chronic. During the acute stage pathological damage is related to the presence of the parasite, whereas in the chronic stage few parasites are found. In recent years the roles of tumor necrosis factor, gamma interferon, and the interleukins in the pathogenesis of this infection have been reported. The common manifestations of chronic cardiomyopathy are arrhythmias and thromboembolic events. Autoimmune, neurogenic, and microvascular factors may be important in the pathogenesis of the cardiomyopathy. The gastrointestinal tract is another important target, and "mega syndromes" are common manifestations. The diagnosis and treatment of this infection are active areas of investigation. New serological and molecular biological techniques have improved the diagnosis of chronic infection. Exacerbations of T. cruzi infection have been reported for patients receiving immuno-suppressive therapy and for those with AIDS.

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“…These concentrations did not affect the faint cytoplasmic fluorescence up to 1 h after exposure. Lower concentrations (1 jiM CM, 3.2 jiM TFP, and 10 ,uM CPZ) did not eliminate mitochondrial fluorescence after 1 h; 100 iM TFP-SO had no effect on mitochondrial fluorescence.These studies were done to answer two questions: do calmodulin inhibitors have therapeutic potential as antimalarial agents, as suggested for other parasitic protozoa (29,30,36,40,41,45) …”

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confidence: 99%

“…These studies were done to answer two questions: do calmodulin inhibitors have therapeutic potential as antimalarial agents, as suggested for other parasitic protozoa (29,30,36,40,41,45) …”

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Effect of calmodulin inhibitors on viability and mitochondrial potential of Plasmodium falciparum in culture

Geary¹,

Divo²,

Jensen³

1986

Antimicrob Agents Chemother

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mmol) (both from New England Nuclear Corp.). Parasites were harvested, and radioactivity was determined as previously described (11,17).Epifluorescence microscopy was used to monitor rhodamine 123 (RH123) retention in parasite mitochondria as previously described (12) Fig. 1 RH123 concentrated in the parasite mitochondrion (Fig. 2A); 5 juM CM eliminated this fluorescence within 5 min (Fig. 2B). Similar results were observed with 32 jiM CPZ and 10 jiM TFP. These concentrations did not affect the faint cytoplasmic fluorescence up to 1 h after exposure. Lower concentrations (1 jiM CM, 3.2 jiM TFP, and 10 ,uM CPZ) did not eliminate mitochondrial fluorescence after 1 h; 100 iM TFP-SO had no effect on mitochondrial fluorescence.These studies were done to answer two questions: do calmodulin inhibitors have therapeutic potential as antimalarial agents, as suggested for other parasitic protozoa (29,30,36,40,41,45)

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Calmodulin and Ca2+-dependent cyclic AMP phosphodiesterase activity in Trypanosoma cruzi

Cited by 62 publications

References 25 publications

Cloning and characterization of a cAMP-specific phosphodiesterase (TbPDE2B) from Trypanosoma brucei

Cloning and characterization of a cAMP-specific phosphodiesterase (TbPDE2B) from Trypanosoma brucei

Chagas' disease

Effect of calmodulin inhibitors on viability and mitochondrial potential of Plasmodium falciparum in culture

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