Role of Melatonin in the Synchronization of Asexual Forms in the Parasite Plasmodium falciparum

Abstract

The indoleamine compound melatonin has been extensively studied in the regulation of the circadian rhythm in nearly all vertebrates. The effects of melatonin have also been studied in Protozoan parasites, especially in the synchronization of the human malaria parasite Plasmodium falciparum via a complex downstream signalling pathway. Melatonin activates protein kinase A (PfPKA) and requires the activation of protein kinase 7 (PfPK7), PLC-IP₃, and a subset of genes from the ubiquitin-proteasome system. In other parasites, such as Trypanosoma cruzi and Toxoplasma gondii, melatonin increases inflammatory components, thus amplifying the protective response of the host's immune system and affecting parasite load. The development of melatonin-related indole compounds exhibiting antiparasitic properties clearly suggests this new and effective approach as an alternative treatment. Therefore, it is critical to understand how melatonin confers stimulatory functions in host-parasite biology.

Keywords: Apicomplexa; melatonin; rhythm; signalling.

Figure 1

Melatonin signalling in P. Falciparum. Melatonin stimulates the cleavage of PIP₂ by phospholipase C (PLC) to produce IP₃, which activates IP₃R to release Ca²⁺ in the cytosol. Simultaneously, melatonin also activates the production of cAMP, which triggers the downstream PfPKA signalling cascade. On the other hand, the orphan kinase PfPK7 is upregulated by melatonin and is linked with the parasite’s proteasomal activation. RBCM—RBC membrane; PVM—Parasitophorous vacuole membrane; PPM—Parasite plasma membrane; Mel—Melatonin; MelR—Melatonin receptor (hypothetical); AC—Adenylyl cyclase; PLC—Phospholipase C; PIP₂—Phosphatidylinositol-4,5-biphosphate; IP₃—Inositol-1,4,5-triphosphate; DAG—Diacylglycerol; ER—Endoplasmic reticulum; N—Nucleus; SERCA—sarco/endoplasmic reticulum Ca²⁺—ATPase.