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

Abstract

BackgroundG 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.ResultsApplication 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.ConclusionsGenome-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.

Evidence for a Bacterial Lipopolysaccharide-Recognizing G-Protein-Coupled Receptor in the Bacterial Engulfment by Entamoeba histolytica

“…With our GPCR search algorithm designated the transmembrane-focused support vector machine (TMf-SVM), we explored the E. histolytica genome for GPCR-like sequences, as previously described for other eukaryotes (20). Expression of these sequences was then analyzed within the Entamoeba database (www.amoebadb.org; version 2.0), using data from expressed sequence tags (ESTs) and microarrays.…”

“…Identity of eight putative and novel E. histolytica GPCRs uncovered when we used TMf-SVM (20). Expression of each receptor in E. histolytica is also shown, as determined from EST and microarray studies (www.amoebadb.org).…”

Exploring the function of protein kinases in schistosomes: perspectives from the laboratory and from comparative genomics

“…They also possess upstream receptors and endogenous signaling molecules (Osman et al, 2006; Khayath et al, 2007; Berriman et al, 2009; Oliveira et al, 2009; The Schistosoma japonicum Genome Sequencing and Functional Analysis Consortium, 2009; Zamanian et al, 2011; Young et al, 2012). Importantly, in the context of host-parasite interactions, schistosomes have been shown to respond to human insulin (You et al, 2009), transforming growth factor (TGF)-β 1 (Osman et al, 2006), and tumor necrosis factor (TNF)-α (Oliveira et al, 2009), demonstrating that they can bind host signaling molecules and transduce input signals through intact pathways.…”

Biogenic amines and the control of neuromuscular signaling in schistosomes

“…Initially, the sequence analysis identified a total of 16 putative BA receptors, all rhodopsin-like GPCRs (Berriman et al 2009). A more recent bioinformatics study suggests the number of BA receptors may be even larger, possibly as many as 24 (Zamanian et al 2011), though some of these are partial sequences that may not encode functional receptors. Many BA-like GPCRs have also been detected in the genome of S. japonicum (The Schistosoma Japonicum Genome Sequencing and Functional Analysis Consortium 2009) and the free-living flatworm, Schmidtea mediterranea (Robb et al 2007;Zamanian et al 2011) suggesting this is an important signaling mechanism across the phylum.…”