Gametogenesis in malaria parasites is mediated by the cGMP-dependent protein kinase.
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.
Department of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom.
Louisa
L
McRobert
Cathy J
CJ
Taylor
Wensheng
W
Deng
Quinton L
QL
Fivelman
Ross M
RM
Cummings
Spencer D
SD
Polley
Oliver
O
Billker
David A
DA
Baker
D000818:Animals; D002118:Calcium; D009033:Culicidae; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology*; D005718:Gametogenesis; D006801:Humans; D008018:Life Cycle Stages; D010963:Plasmodium falciparum / Q000502:physiology*; D015398:Signal Transduction; D014977:Xanthurenates / Q000494:pharmacology
D014977:Xanthurenates; C028330:xanthurenic acid; D017869:Cyclic GMP-Dependent Protein Kinases; D002118:Calcium