| Title | The malaria parasite cGMP-dependent protein kinase plays a central role in blood stage schizogony. | | Author(s) | Taylor HM, McRobert L, Grainger M, Sicard A, Dluzewski AR, Hopp CS, Holder AA, Baker DA | | Institution | Wellcome Centre for Molecular Parasitology, University of Glasgow, Glasgow, UK; London School of Hygiene & Tropical Medicine, London, UK; MRC National Institute for Medical Research, Mill Hill, London, UK. | | Source | Eukaryot Cell 2009 Nov 13. | | Abstract | A role for the Plasmodium falciparum 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 tri-substituted 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 post invasion and segmented schizonts were able to form. However, synchronised schizonts treated with compound 1 for >/=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 utilised 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 signalling 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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19915077 |
|
