A G-Protein-Coupled Receptor Modulates Gametogenesis via PKG-Mediated Signaling Cascade in Plasmodium berghei.

Gametogenesis is essential for malaria parasite transmission, but the molecular mechanism of this process remains to be refined. Here, we identified a G-protein-coupled receptor 180 (GPR180) that plays a critical role in signal transduction during gametogenesis in The P. berghei GPR180 was predominantly expressed in gametocytes and ookinetes and associated with the plasma membrane in female gametes and ookinetes. Knockout of (Δ) had no noticeable effect on blood-stage development but impaired gamete formation and reduced transmission of the parasites to mosquitoes. Transcriptome analysis revealed that a large proportion of the dysregulated genes in the Δ gametocytes had assigned functions in cyclic nucleotide signal transduction. In the Δ gametocytes, the intracellular cGMP level was significantly reduced, and the cytosolic Ca mobilization showed a delay and a reduction in the magnitude during gametocyte activation. These results suggest that PbGPR180 functions upstream of the cGMP-protein kinase G-Ca signaling pathway. In line with this functional prediction, the PbGPR180 protein was found to interact with several transmembrane transporter proteins and the small GTPase Rab6 in activated gametocytes. Allele replacement of with the P. vivax ortholog showed equal competence of the transgenic parasite in sexual development, suggesting functional conservation of this gene in spp. Furthermore, an anti-PbGPR180 monoclonal antibody and the anti-PvGPR180 serum possessed robust transmission-blocking activities. These results indicate that GPR180 is involved in signal transduction during gametogenesis in malaria parasites and is a promising target for blocking parasite transmission. Environmental changes from humans to mosquitoes activate gametogenesis of the malaria parasite, an obligative process for parasite transmission, but how the signals are relayed remains poorly understood. Here, we show the identification of a G-protein-coupled receptor, GPR180, and the characterization of its function in gametogenesis. In P. berghei, GPR180 is dispensable for asexual development and gametocytogenesis, but its deletion impairs gametogenesis and reduces transmission to mosquitoes. GPR180 appears to function upstream of the cGMP-protein kinase G-Ca signaling pathway and is required for the maximum activity of this pathway. Genetic complementation shows that the GPR180 ortholog from the human malaria parasite P. vivax was fully functional in P. berghei, indicating functional conservation of GPR180 in spp. With predominant expression and membrane association of GPR180 in sexual stages, GPR180 is a promising target for blocking transmission, and antibodies against GPR180 possess robust transmission-blocking activities.