Abstract
Cyclic Nucleotide Signaling Pathways in Apicomplexan Parasites Provide a Valuable Source for Novel Drug Targets
Highlights
Malaria is one of the most important disabling human, tropical disease caused by different Plasmodium species, which are protozoan parasites belonging to the Apicomplexa
The Apicomplexan parasites have a plastid like structure the “apicoplast” and comprise the genera Plasmodium, Toxoplasma and Cryptosporidium causing malaria, toxoplasmosis, and cryptosporidiosis
The cyclic nucleotides cAMP and cGMP play an essential role in proliferation and differentiation which enables them to adapt to various environmental stimuli in the host cell
Summary
Plasmodium has a Non-canonical cAMPregulated Pathway without G-proteins and GPCRs. Malaria is one of the most important disabling human, tropical disease caused by different Plasmodium species, which are protozoan parasites belonging to the Apicomplexa. Receptor activation leads to the exchange of GDP to GTP from the G-α subunit and in turn to the dissociation from the G-ßχ dimer Both subunits are capable of independent signaling to downstream effectors like adenylyl cyclases or guanylcyclases which are responsible for cyclization of ATP/GTP to cAMP/cGMP. CAMP in turn activates the formation of Rap-GDP to Rap-GTP [14] triggering phospholipase C (PLC) to produce inositol triphosphate (IP3) that binds to the IP3 (IP3-R) receptor on the ER This leads to a release in Ca-ions which bind to calcineurin and activation of Calcium dependent protein kinase 1 (CDPK1) that facilitates parasite invasion. In contrast to the mammalian host, PKAc lacks a dimerization domain responsible for the interaction with PKA activating proteins. A second, important feature of PKG is the linkage to the nucleotide exchange pathway (EPAC) since it acts through CDPK1 (Figure 1B)
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