Bioaminergic signaling in parasitic flatworms: a perspective for linking GPCRs to behavior and drug discovery

Bioaminergic signaling regulates behaviors that are central to parasite survival, including movement, attachment, feeding, pairing, and reproduction, yet the molecular pathways linking bioamines to these phenotypes remain incompletely defined in parasitic flatworms. In this Perspective, we propose a pathway-to-phenotype framework for organizing future studies of flatworm aminergic signaling. This framework links six interconnected areas of investigation: the bioamine ligand, the receptor or transporter that detects or clears it, the downstream signaling pathway, the relevant cell type or tissue, the experimental perturbation used to test function, and the resulting parasite phenotype. Serotonin signaling through Sm5HTR in Schistosoma mansoni provides the clearest current example, connecting receptor activation to cAMP signaling, nervous-system localization, and movement. By contrast, dopaminergic, histaminergic, octopaminergic, tyraminergic, transporter-associated, and non-schistosome flatworm systems remain less completely mapped. We highlight these and other gaps, and discuss how comparative functional profiling across parasite lineages could reveal conserved signaling principles, parasite-selective pharmacology, and new opportunities for anthelmintic discovery.