title: Ubiquitin proteasome system and the atypical kinase PfPK7 are involved in melatonin signaling in Plasmodium falciparum.
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.
authors.affiliation: Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Fernanda C
authors.initials: FC
authors.lastname: Koyama
authors.forename: Ramira Y
authors.initials: RY
authors.lastname: Ribeiro
authors.forename: Julio L
authors.initials: JL
authors.lastname: Garcia
authors.forename: Mauro F
authors.initials: MF
authors.lastname: Azevedo
authors.forename: Debopam
authors.initials: D
authors.lastname: Chakrabarti
authors.forename: Célia R S
authors.initials: CR
authors.lastname: Garcia
mesh_terms: D000818:Animals; D016778:Malaria, Falciparum; D008550:Melatonin / Q000494:pharmacology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*
chemical_list: D015800:Protozoan Proteins; D025801:Ubiquitin; C503375:PK7 protein, Plasmodium falciparum; D020929:Mitogen-Activated Protein Kinase Kinases; D046988:Proteasome Endopeptidase Complex; D008550:Melatonin