Journal
PLOS BIOLOGY
Volume 6, Issue 6, Pages 1243-1252Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pbio.0060139
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Funding
- Medical Research Council [G0501670, 012174] Funding Source: Medline
- Wellcome Trust [066742] Funding Source: Medline
- Medical Research Council [G0501670] Funding Source: researchfish
- MRC [G0501670] Funding Source: UKRI
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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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