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Since standard treatment of schistosomiasis relies on a single drug, praziquantel, alternative drugs are needed. G protein-coupled receptors (GPCRs) represent promising targets for new anthelmintics. Although GPCRs represent a prominent receptor class in schistosomes, functional studies are limited just as knowledge about their ligands. Candidate ligands are neuropeptides acting as neurotransmitters, neuromodulators, or hormones in the nervous system. Transcriptomics studies in\n            <jats:italic>Schistosoma mansoni<\/jats:italic>\n            indicated that nearly all neuropeptide genes (\n            <jats:italic>Sm_npps<\/jats:italic>\n            ) and a subgroup of GPCRs exhibited a sex- and pairing-dependent expression profile. Among these was the rhodopsin orphan GPCR20 (\n            <jats:italic>Sm<\/jats:italic>\n            GPCR20), which we characterized in our study. Using a yeast two-hybrid-based approach, we identified specific interactions between\n            <jats:italic>Sm<\/jats:italic>\n            GPCR20 and two neuropeptides\n            <jats:italic>Sm<\/jats:italic>\n            NPP26 and\n            <jats:italic>Sm<\/jats:italic>\n            NPP40. As analyzed by qRT-PCR,\n            <jats:italic>Smgpcr20<\/jats:italic>\n            ,\n            <jats:italic>Smnpp26<\/jats:italic>\n            , and\n            <jats:italic>Smnpp40<\/jats:italic>\n            showed sex- and\/or pairing-influenced expression. Whole-mount\n            <jats:italic>in situ<\/jats:italic>\n            hybridization exhibited transcripts of these genes in neuronal cells, subtegumental area, and parenchyma of both sexes. Furthermore, we received indication for co-localization of transcripts of these genes in the anterior \u201chead\u201d region of single-sex females and in particular patterns along the worm body indicating neuronal expression. RNA interference (RNAi) with combinations of double-stranded RNAs against the three genes resulted in reduced egg production. Confocal microscopy revealed morphologic changes in the female gonads. Furthermore, RNAi in first-time paired females caused a reduced length of females after double knockdown of\n            <jats:italic>Sm<\/jats:italic>\n            GPCR20 and\n            <jats:italic>Sm<\/jats:italic>\n            NPP26 and changes in the ovary. In addition, we found reduced transcript levels of egg formation-associated and gonad-specifically transcribed genes and the stem-cell marker\n            <jats:italic>nanos-1<\/jats:italic>\n            . The obtained results suggest that\n            <jats:italic>Sm<\/jats:italic>\n            NPP26 and\n            <jats:italic>Sm<\/jats:italic>\n            NPP40 are potential ligands of\n            <jats:italic>Sm<\/jats:italic>\n            GPCR20 and that this GPCR in combination with both neuropeptides affects egg production, oogenesis, and growth of\n            <jats:italic>S. mansoni<\/jats:italic>\n            females.\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              Schistosomes cause schistosomiasis, one of the neglected tropical diseases as defined by the WHO. For decades, the treatment of schistosomiasis relies on a single drug, praziquantel. Due to its wide use, there is justified fear of resistance against this drug, and a vaccine is not available. Besides its biological relevance in signal transduction processes, the class of G protein-coupled receptors (GPCRs) is also well suited for drug design. Against this background, we characterized one GPCR of\n              <jats:italic>Schistosoma mansoni<\/jats:italic>\n              ,\n              <jats:italic>Sm<\/jats:italic>\n              GPCR20, at the molecular and functional level. We identified two potential neuropeptides (NPPs) as ligands,\n              <jats:italic>Sm<\/jats:italic>\n              NPP26 and\n              <jats:italic>Sm<\/jats:italic>\n              NPP40, and unraveled their roles, in combination with\n              <jats:italic>Sm<\/jats:italic>\n              GPCR20, in neuronal processes controlling egg production, oogenesis, and growth of\n              <jats:italic>S. mansoni<\/jats:italic>\n              females. Since eggs are closely associated with the pathogenesis of schistosomiasis, our results contribute to the understanding of processes leading to egg production in schistosomes, which is under the control of pairing in this exceptional parasite.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/spectrum.02193-23","type":"journal-article","created":{"date-parts":[[2023,12,4]],"date-time":"2023-12-04T14:01:48Z","timestamp":1701698508000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":6,"title":["Rhodopsin orphan GPCR20 interacts with neuropeptides and directs growth, sexual differentiation, and egg production in female\n            <i>Schistosoma mansoni<\/i>"],"prefix":"10.1128","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5038-6606","authenticated-orcid":false,"given":"Xuesong","family":"Li","sequence":"first","affiliation":[{"name":"Institute for Parasitology, BFS, Justus Liebig 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