The malaria parasite cyclic GMP-dependent protein kinase plays a central role in blood-stage schizogony

Taylor, H.M., McRobert, L., Grainger, M., Sicard, A., Dluzewski, A.R., Hopp, C.S., Holder, A.A. and Baker, D.A. (2010) The malaria parasite cyclic GMP-dependent protein kinase plays a central role in blood-stage schizogony. Eukaryotic Cell, 9(1), pp. 37-45. (doi: 10.1128/EC.00186-09)

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 ≥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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Taylor, Dr Helen and Sicard, Miss Audrey
• Authors: Taylor, H.M., McRobert, L., Grainger, M., Sicard, A., Dluzewski, A.R., Hopp, C.S., Holder, A.A., and Baker, D.A.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Eukaryotic Cell
• ISSN: 1535-9778
• ISSN (Online): 1535-9786
• Published Online: 13 November 2009
• Copyright Holders: Copyright © 2010, American Society for Microbiology
• First Published: First published in Eukaryotic Cell 2010, 9(1):37-45.
• Publisher Policy: Paid Open Access