Division of Cell & Molecular Biology
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Structure-function analysis of xanthurenic acid as activator of gametogenesis in Plasmodium
Transmission of Plasmodium spp. requires the initial differentiation of sexual parasite stages into male and female gametes upon blood-feeding by the mosquito. Midgut-derived xanthurenic acid (XA) and a drop in temperature are sufficient to induce gametogenesis of Plasmodium parasites in vitro. A first sign of activation of gametocytes is the measurable rise in intracellular calcium concentration. The order of events upstream of this calcium signal is not understood and particularly the predicted XA receptor has remained elusive. To probe these early signalling events we screened 2000 known drugs and natural products and small molecules for their ability to mobilise and inhibit calcium in Plasmodium berghei gametocytes. Several gametocyte-specific activators and inhibitors of XA-induced calcium release were identified, some of which with the expected properties of xanthurenic acid receptor agonists and antagonists.The most potent activators and a competitive inhibitor belong to the same functional class of molecules and provide insight into the structural requirements for receptor activation. These compounds will prove valuable tools in the identification of the XA receptor and could be exploited for the development of transmission-blocking drugs.