Unique pharmacological properties of serotoninergic G-protein coupled receptors from cestodes

Abstract

BackgroundCestodes are a diverse group of parasites, some of them being agents of neglected diseases. In cestodes, little is known about the functional properties of G protein coupled receptors (GPCRs) which have proved to be highly druggable targets in other organisms. Notably, serotoninergic G-protein coupled receptors (5-HT GPCRs) play major roles in key functions like movement, development and reproduction in parasites.Methodology/Principal findingsThree 5-HT GPCRs from Echinococcus granulosus and Mesocestoides corti were cloned, sequenced, bioinformatically analyzed and functionally characterized. Multiple sequence alignment with other GPCRs showed the presence of seven transmembrane segments and conserved motifs but interesting differences were also observed. Phylogenetic analysis grouped these new sequences within the 5-HT7 clade of GPCRs. Molecular modeling showed a striking resemblance in the spatial localization of key residues with their mammalian counterparts. Expression analysis using available RNAseq data showed that both E. granulosus sequences are expressed in larval and adult stages. Localization studies performed in E. granulosus larvae with a fluorescent probe produced a punctiform pattern concentrated in suckers. E. granulosus and M. corti larvae showed an increase in motility in response to serotonin. Heterologous expression revealed elevated levels of cAMP production in response to 5-HT and two of the GPCRs showed extremely high sensitivity to 5-HT (picomolar range). While each of these GPCRs was activated by 5-HT, they exhibit distinct pharmacological properties (5-HT sensitivity, differential responsiveness to ligands).Conclusions/SignificanceThese data provide the first functional report of GPCRs in parasitic cestodes. The serotoninergic GPCRs characterized here may represent novel druggable targets for antiparasitic intervention.

Transcriptomic Features of Echinococcus granulosus Protoscolex during the Encystation Process

“…Gene-encoding proteins involved in several signaling pathways, like putative G-protein coupled receptor (GPCR), tyrosine kinases, and serine/threonine protein kinase were predominantly up-regulated during the encystation process of PSCs. These signaling pathways play major roles in key functions, including movement, development, and reproduction in parasites [36]. Our findings are consistent with those of previous studies on S. mekongi [24] and S. japonicum [37].…”

Transcriptomic analysis of the Echinococcus granulosus protoscolex in the encystation process

“…Genes encoding proteins involved in several signaling pathways, such as putative G-protein coupled receptor (GPCR), tyrosine kinases, and serine/threonine protein kinase were predominantly upregulated during encystation process of PSCs. These signaling pathways play major roles in key functions like movement, development, and reproduction in parasites [40]. Our findings are paralled to the previous studies of S. mekongi [27] and S.japonicum [41].…”

Invertebrate serotonin receptors: a molecular perspective on classification and pharmacology

“…Receptors cloned from cestodes were activated by the nonspecific agonists egotamine and LSD, though the latter had antagonist rather than agonist activity at 5-HT 7bEch receptors. Two cestode receptors, 5-HT 7bEch and 5-HT 7Mes , responded to 5-HT with EC 50 values in the picomolar range, indicating unusually high sensitivity to the transmitter (Camicia et al, 2018).…”

“…In addition, 5-HT 7 receptors have been described in flatworms ( phylum Platyhelminthes; see Glossary), and this receptor family appears to be the dominant clade in these organisms. Multiple sequences have been found in the planarian Dugesia japonica (Saitoh et al, 1997;Nishimura et al, 2009), the parasitic worm Schistosoma mansoni (Patocka et al, 2014;Chan et al, 2016a) and the cestodes Echinococcus granulosus and Mesocestoides corti (Camicia et al, 2018). Genome searches predict the presence of additional 5-HT receptors in Platyhelminthes (Chan et al, 2015;Patocka et al, 2014), but they have not yet been characterized.…”