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Background  G protein-coupled receptors (GPCRs) constitute one of the largest groupings of eukaryotic proteins, and represent a particularly lucrative set of pharmaceutical targets. They play an important role in eukaryotic signal transduction and physiology, mediating cellular responses to a diverse range of extracellular stimuli. The phylum Platyhelminthes is of considerable medical and biological importance, housing major pathogens as well as established model organisms. The recent availability of genomic data for the human blood fluke  Schistosoma mansoni  and the model planarian  Schmidtea mediterranea  paves the way for the first comprehensive effort to identify and analyze GPCRs in this important phylum.    Results  Application of a novel transmembrane-oriented approach to receptor mining led to the discovery of 117  S. mansoni  GPCRs, representing all of the major families; 105  Rhodopsin , 2  Glutamate , 3  Adhesion , 2  Secretin  and 5  Frizzled . Similarly, 418  Rhodopsin , 9  Glutamate , 21  Adhesion , 1  Secretin  and 11  Frizzled S. mediterranea  receptors were identified. Among these, we report the identification of novel receptor groupings, including a large and highly-diverged Platyhelminth-specific  Rhodopsin  subfamily, a planarian-specific  Adhesion -like family, and atypical  Glutamate -like receptors. Phylogenetic analysis was carried out following extensive gene curation. Support vector machines (SVMs) were trained and used for ligand-based classification of full-length  Rhodopsin  GPCRs, complementing phylogenetic and homology-based classification.    Conclusions  Genome-wide investigation of GPCRs in two platyhelminth genomes reveals an extensive and complex receptor signaling repertoire with many unique features. This work provides important sequence and functional leads for understanding basic flatworm receptor biology, and sheds light on a lucrative set of anthelmintic drug targets.

The repertoire of G protein-coupled receptors in the human parasite Schistosoma mansoni and the model organism Schmidtea mediterranea