The gametocyte-activating factor xanthurenic acid stimulates an increase in membrane-associated guanylyl cyclase activity in the human malaria parasite Plasmodium falciparum

Sex is an obligate step in the life cycle of the malaria parasite and occur s in the midgut of the mosquito vector. With both Plasmodium falciparum and Plasmodium berghei, the tryptophan metabolite xanthurenic acid induces the release of motile male gametes from red blood cells (exflagellation), a pr erequisite for fertilization. The addition of cGMP or phosphodiesterase inh ibitors to cultures of mature gametocytes has also been shown to stimulate exflagellation. Here, we demonstrate that there is a guanylyl cyclase activ ity associated with mature P. falciparum, gametocyte membrane preparations, which is dependent on the presence of Mg2+/Mn2+ but is inhibited by Ca2+. Significantly, this activity is increased on addition of xanthurenic acid. In contrast, a xanthurenic acid precursor (3-hydroxykynurenine), which is n ot an inducer of exflagellation, does not induce this guanylyl cyclase acti vity. These results therefore suggest that xanthurenic acid-induced exflage llation may be mediated by activation of the parasite cGMP signalling pathw ay.