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

CAMICIA, FEDERICO; CELENTANO, ANA M.; JOHNS, MALCOLM E.; CHAN, JOHN D.; MALDONADO, LUCAS; VACA, HUGO; DI SIERVI, NICOLÁS; KAMENETZKY, LAURA; GAMO, ANA M.; ORTEGA-GUTIERREZ, SILVIA; MARTIN-FONTECHA, MAR; DAVIO, CARLOS; MARCHANT, JONATHAN S.; ROSENZVIT, MARA C.

PLOS NEGLECTED TROPICAL DISEASES

PUBLIC LIBRARY SCIENCE

Año: 2018 vol. 12

1935-2735

Background:Cestodes are a diverse group of parasites, some of them being agents of neglected dis-eases. In cestodes, little is known about the functional properties of G protein coupledreceptors (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 keyfunctions like movement, development and reproduction in parasites.Methodology/Principal findings:Three 5-HT GPCRs from Echinococcus granulosus and Mesocestoides corti were cloned,sequenced, bioinformatically analyzed and functionally characterized. Multiple sequencealignment with other GPCRs showed the presence of seven transmembrane segments andconserved motifs but interesting differences were also observed. Phylogenetic analysisgrouped these new sequences within the 5-HT7 clade of GPCRs. Molecular modelingshowed 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 patternconcentrated in suckers. E. granulosus and M. corti larvae showed an increase in motilityin response to serotonin. Heterologous expression revealed elevated levels of cAMPproduction 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 exhibitdistinct pharmacological properties (5-HT sensitivity, differential responsiveness to ligands).Conclusions/Significance: These data provide the first functional report of GPCRs in parasitic cestodes. The serotoninergic GPCRs characterized here may represent novel druggable targets for antiparasiticintervention.