gametogenesis in malaria parasites is mediated by the cgmp-dependent protein kinase配子形成cgmp-dependent在疟疾寄生虫介导的蛋白激酶.pdfVIP

PLoS BIOLOGY Gametogenesis in Malaria Parasites Is Mediated by the cGMP-Dependent Protein Kinase 1 1 1¤ 1 1 1 Louisa McRobert , Cathy J. Taylor , Wensheng Deng , Quinton L. Fivelman , Ross M. Cummings , Spencer D. Polley , 2 1* Oliver Billker , David A. Baker 1 Department of Infectious and Tropical Diseases, London School of Hygiene Tropical Medicine, London, United Kingdom, 2 Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom Malaria parasite transmission requires differentiation of male and female gametocytes into gametes within a mosquito following a blood meal. A mosquito-derived molecule, xanthurenic acid (XA), can trigger gametogenesis, but the signalling events controlling this process in the human malaria parasite Plasmodium falciparum remain unknown. A role for cGMP was revealed by our observation that zaprinast (an inhibitor of phosphodiesterases that hydrolyse cGMP) stimulates gametogenesis in the absence of XA. Using cGMP-dependent protein kinase (PKG) inhibitors in conjunction with transgenic parasites expressing an inhibitor-insensitive mutant PKG enzyme, we demonstrate that PKG is essential for XA- and zaprinast-induced gametogenesis. Furthermore, we show that intracellular calcium (Ca2þ) is required for differentiation and acts downstream of or in parallel with PKG activation. This work defines a key role for PKG in gametogenesis, elucidates the hierarchy of signalling events governing this process in P. falciparum, and demonstrates the feasibility of selective inhibition of a crucial regulator of the malaria parasite life cycle. Citation: McRobe