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Molecular characterization of the serotonergic transporter from the cestode Echinococcus granulosus: pharmacology and potential role in the nervous system

Abstract

Echinococcus granulosus, the etiological agent of human cystic echinococcosis (formerly known as hydatid disease), represents a serious worldwide public health problem with limited treatment options. The essential role played by the neuromuscular system in parasite survival and the relevance of serotonin (5-HT) in parasite movement and development make the serotonergic system an attractive source of drug targets. In this study, we cloned and sequenced a cDNA coding for the serotonin transporter from E. granulosus (EgSERT). Bioinformatic analyses suggest that EgSERT has twelve transmembrane domains with highly conserved ligand and ionic binding sites but a less conserved allosteric site compared with the human orthologue (HsSERT). Modeling studies also suggest a good degree of conservation of the overall structure compared with HsSERT. Functional and pharmacological studies performed on the cloned EgSERT confirm that this protein is indeed a serotonin transporter. EgSERT is specific for 5-HT and does not transport other neurotransmitters. Typical monoamine transport inhibitors also displayed inhibitory activities towards EgSERT, but with lower affinity than for the human SERT (HsSERT), suggesting a high divergence of the cestode transporter compared with HsSERT. In situ hybridization studies performed in the larval protoscolex stage suggest that EgSERT is located in discrete regions that are compatible with the major ganglia of the serotonergic nervous system. The pharmacological properties, the amino acidic substitutions at important functional regions compared with the HsSERT, and the putative role of EgSERT in the nervous system suggest that it could be an important target for pharmacological intervention.

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Fig. 1

available at the National Center for Biotechnology Information (NCBI) site, the UniProt database (https://www.uniprot.org/proteomes/), and the WormBase Parasite (). The numbers in red at branch points are bootstrap values. The length of the branches is proportional to the genetic distance between sequences (see scale bar)

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Acknowledgements

This work was supported in part by NIH grants to O.V.M. [grant number MH121453] and A.C.K.F. [grant number NS111767]; F.C. was supported by Secretaria de Ciencia y Técnica (UBACyT), Universidad de Buenos Aires, Facultad de Medicina, Argentina, Projecto Programación Científica 2016, [grant number 20020150100160BA].

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Correspondence to Andreia C. K. Fontana.

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Camicia, F., Vaca, H.R., Guarnaschelli, I. et al. Molecular characterization of the serotonergic transporter from the cestode Echinococcus granulosus: pharmacology and potential role in the nervous system. Parasitol Res 121, 1329–1343 (2022). https://doi.org/10.1007/s00436-022-07466-y

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Keywords

  • Serotonin transporter
  • Cestodes
  • Neglected diseases
  • Drug target
  • Pharmacology
  • 5-HT