Characterization of a new type of neuronal 5-HT G-protein coupled receptor in the cestode nervous system.

CAMICIA F; VACA H; PARK, SANG-KYU; BIVONA, AUGUSTO; ARIEL NAIDICH; PREZA M; KOZIOL, URIEL; CELENTANO, ANA M.; MARCHANT, JONATHAN S.; ROSENZVIT M C

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2021

1932-6203

Cestodes are platyhelminth parasites with a wide range of hosts that cause neglected31 diseases. Neurotransmitter signaling is of critical importance for these parasites which32 lack circulatory, respiratory and digestive systems. For example, serotonin (5-HT) and33 serotonergic G-protein coupled receptors (5-HT GPCRs) play major roles in cestode34 motility, development and reproduction. In previous work, we deorphanized a group of35 5-HT7 type GPCRs from cestodes. However, little is known about another type of 5-HT36 GPCR, the 5-HT1 clade, which has been studied in several invertebrate phyla but not in37 platyhelminthes.38 Three putative 5-HT GPCRs from Echinococcus canadensis, Mesocestoides vogae (syn.39 Mesocestoides corti) and Hymenolepis microstoma were cloned, sequenced and40 bioinformatically analyzed. Evidence grouped these new sequences within the 5-HT141 clade of GPCRs but differences in highly conserved GPCR motifs were observed.42 Transcriptomic analysis, heterologous expression and immunolocalization studies were43 performed to characterize the E. canadensis receptor, called Eca-5-HT1a. Functional44 heterologous expression studies showed that Eca-5-HT1a is highly specific for serotonin.45 5-Methoxytryptamine and α-methylserotonin, both known 5-HT GPCR agonists, give46 stimulatory responses whereas methysergide, a known 5-HT GPCR ligand, give47 antagonist responses in Eca-5-HT1a. Mutants obtained by the substitution of key48 predicted residues resulted in severe impairment of receptor activity, confirming that49 indeed, these residues have important roles in receptor function. Immunolocalization50 studies on the protoscolex stage from E. canadensis, showed that Eca-5-HT1a is3localized in branched fibers which 51 correspond to the nervous system of the parasite. The52 patterns of immunoreactive fibers for Eca-5-HT1a and for serotonin were intimately53 intertwined but not identical, suggesting that they are two separate groups of fibers.54 These data provide the first functional, pharmacological and localization report of a55 serotonergic receptor that putatively belongs to the 5-HT1 type of GPCRs in cestodes.56 The serotonergic GPCR characterized here may represent a new target for antiparasitic57 intervention.