title: The malaria parasite cyclic GMP-dependent protein kinase plays a central role in blood-stage schizogony.
abstract: A role for the Plasmodium falciparum cyclic GMP (cGMP)-dependent protein kinase (PfPKG) in gametogenesis in the malaria parasite was elucidated previously. In the present study we examined the role of PfPKG in the asexual blood-stage of the parasite life cycle, the stage that causes malaria pathology. A specific PKG inhibitor (compound 1, a trisubstituted pyrrole) prevented the progression of P. falciparum schizonts through to ring stages in erythrocyte invasion assays. Addition of compound 1 to ring-stage parasites allowed normal development up to 30 h postinvasion, and segmented schizonts were able to form. However, synchronized schizonts treated with compound 1 for > or =6 h became large and dysmorphic and were unable to rupture or liberate merozoites. To conclusively demonstrate that the effect of compound 1 on schizogony was due to its selective action on PfPKG, we utilized genetically manipulated P. falciparum parasites expressing a compound 1-insensitive PfPKG. The mutant parasites were able to complete schizogony in the presence of compound 1 but not in the presence of the broad-spectrum protein kinase inhibitor staurosporine. This shows that PfPKG is the primary target of compound 1 during schizogony and provides direct evidence of a role for PfPKG in this process. Discovery of essential roles for the P. falciparum PKG in both asexual and sexual development demonstrates that cGMP signaling is a key regulator of both of these crucial life cycle phases and defines this molecule as an exciting potential drug target for both therapeutic and transmission blocking action against malaria.
authors.affiliation: Wellcome Centre for Molecular Parasitology, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Taylor
authors.forename: Louisa
authors.initials: L
authors.lastname: McRobert
authors.forename: Munira
authors.initials: M
authors.lastname: Grainger
authors.forename: Audrey
authors.initials: A
authors.lastname: Sicard
authors.forename: Anton R
authors.initials: AR
authors.lastname: Dluzewski
authors.forename: Christine S
authors.initials: CS
authors.lastname: Hopp
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Holder
authors.forename: David A
authors.initials: DA
authors.lastname: Baker
mesh_terms: D000818:Animals; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D008018:Life Cycle Stages / Q000502:physiology; D008288:Malaria / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000472:pathogenicity / Q000502:physiology*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D017869:Cyclic GMP-Dependent Protein Kinases