cAMP-Dependent Signaling Pathways as Potential Targets for Inhibition of Plasmodium falciparum Blood Stages

Lasonder, Edwin, More, Kunal, Singh, Shailja, Haidar, Malak, Bertinetti, Daniela, Kennedy, Eileen J., Herberg, Friedrich W., Holder, Anthony A., Langsley, Gordon and Chitnis, Chetan E. (2021) cAMP-Dependent Signaling Pathways as Potential Targets for Inhibition of Plasmodium falciparum Blood Stages. Frontiers in Microbiology, 12. p. 684005. ISSN 1664-302X

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We review the role of signaling pathways in regulation of the key processes of merozoite egress and red blood cell invasion by Plasmodium falciparum and, in particular, the importance of the second messengers, cAMP and Ca2+, and cyclic nucleotide dependent kinases. cAMP-dependent protein kinase (PKA) is comprised of cAMP-binding regulatory, and catalytic subunits. The less well conserved cAMP-binding pockets should make cAMP analogs attractive drug leads, but this approach is compromised by the poor membrane permeability of cyclic nucleotides. We discuss how the conserved nature of ATP-binding pockets makes ATP analogs inherently prone to off-target effects and how ATP analogs and genetic manipulation can be useful research tools to examine this. We suggest that targeting PKA interaction partners as well as substrates, or developing inhibitors based on PKA interaction sites or phosphorylation sites in PKA substrates, may provide viable alternative approaches for the development of anti-malarial drugs. Proximity of PKA to a substrate is necessary for substrate phosphorylation, but the P. falciparum genome encodes few recognizable A-kinase anchor proteins (AKAPs), suggesting the importance of PKA-regulatory subunit myristylation and membrane association in determining substrate preference. We also discuss how Pf14-3-3 assembles a phosphorylation-dependent signaling complex that includes PKA and calcium dependent protein kinase 1 (CDPK1) and how this complex may be critical for merozoite invasion, and a target to block parasite growth. We compare altered phosphorylation levels in intracellular and egressed merozoites to identify potential PKA substrates. Finally, as host PKA may have a critical role in supporting intracellular parasite development, we discuss its role at other stages of the life cycle, as well as in other apicomplexan infections. Throughout our review we propose possible new directions for the therapeutic exploitation of cAMP-PKA-signaling in malaria and other diseases caused by apicomplexan parasites.

Item Type: Article
Additional Information: Funding information: This work was supported by grants from the French Government Agence Nationale de la Recherche (ANR-17-CE15-0010 and ANR-11-LABEX-0024-PARAFRAP to CC), Deutsche Forschungsgemeinschaft (DFG, Grant He1818/10, to FH), and Federal Ministry of Education and Research, Germany (TargetRD, FKZ: 16GW0270 to FH). AH was supported by the Francis Crick Institute (FC001097), with core funding from Cancer Research UK (FC001097), UK Medical Research Council (FC001097), and Wellcome Trust (FC001097).
Uncontrolled Keywords: cAMP, PKA, falciparum, merozoite, invasion
Subjects: B900 Others in Subjects allied to Medicine
C100 Biology
C700 Molecular Biology, Biophysics and Biochemistry
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: John Coen
Date Deposited: 07 Jun 2021 10:24
Last Modified: 31 Jul 2021 11:00

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