Gametogenesis in Malaria Parasites Is Mediated by the cGMP-Dependent Protein Kinase |
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Authors: | Louisa McRobert Louisa McRobert Louisa McRobert Louisa McRobert Louisa McRobert Louisa McRobert Louisa McRobert Louisa McRobert |
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Affiliation: | 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 |
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Abstract: | 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 (Ca2+) 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. |
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