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Ubiquitin proteasome system and the atypical kinase PfPK7 are involved in melatonin signaling in Plasmodium falciparum

Authors

  • Fernanda C. Koyama,

    1. Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
    2. Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil
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  • Ramira Y. Ribeiro,

    1. Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
    2. Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil
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  • Julio L. Garcia,

    1. Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil
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  • Mauro F. Azevedo,

    1. Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
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  • Debopam Chakrabarti,

    1. Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL, USA
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  • Célia R. S. Garcia

    1. Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil
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Address reprint requests to Célia Regina da Silva Garcia, Rua do Matão, travessa 14, n. 321. Cidade Universitária, CEP 05508-090, São Paulo, Brazil.
E-mail: cgarcia@usp.br

Abstract

Abstract:  We previously reported that melatonin modulates the Plasmodium falciparum erythrocytic cycle by increasing schizont stage population as well as diminishing ring stage population. In addition, the importance of calcium and cAMP in melatonin signaling pathway in P. falciparum was also demonstrated. Nevertheless, the molecular effectors of the indoleamine signaling pathway remain elusive. We now demonstrate by real-time PCR that melatonin treatment up-regulates genes related to ubiquitin/proteasome system (UPS) components and that luzindole, a melatonin receptor antagonist, inhibits UPS transcription modulation. We also show that protein kinase PfPK7, a P. falciparum orphan kinase, plays a crucial role in the melatonin transduction pathway, since following melatonin treatment of P. falciparum parasites where pfpk7 gene is disrupted (pfpk7 parasites) (i) the ratio of asexual stages remain unchanged, (ii) the increase in cytoplasmatic calcium in response to melatonin was strongly diminished and (iii) up-regulation of UPS genes did not occur. The wild-type melatonin-induced alterations in cell cycle features, calcium rise and UPS gene transcription were restored by re-introduction of a functional copy of the pfpk7 gene in the pfpk7 parasites.

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