Serotonin Signaling in Schistosoma mansoni: A Serotonin–Activated G Protein-Coupled Receptor Controls Parasite Movement

Abstract

Serotonin is an important neuroactive substance in all the parasitic helminths. In Schistosoma mansoni, serotonin is strongly myoexcitatory; it potentiates contraction of the body wall muscles and stimulates motor activity. This is considered to be a critical mechanism of motor control in the parasite, but the mode of action of serotonin is poorly understood. Here we provide the first molecular evidence of a functional serotonin receptor (Sm5HTR) in S. mansoni. The schistosome receptor belongs to the G protein-coupled receptor (GPCR) superfamily and is distantly related to serotonergic type 7 (5HT7) receptors from other species. Functional expression studies in transfected HEK 293 cells showed that Sm5HTR is a specific serotonin receptor and it signals through an increase in intracellular cAMP, consistent with a 5HT7 signaling mechanism. Immunolocalization studies with a specific anti-Sm5HTR antibody revealed that the receptor is abundantly distributed in the worm's nervous system, including the cerebral ganglia and main nerve cords of the central nervous system and the peripheral innervation of the body wall muscles and tegument. RNA interference (RNAi) was performed both in schistosomulae and adult worms to test whether the receptor is required for parasite motility. The RNAi-suppressed adults and larvae were markedly hypoactive compared to the corresponding controls and they were also resistant to exogenous serotonin treatment. These results show that Sm5HTR is at least one of the receptors responsible for the motor effects of serotonin in S. mansoni. The fact that Sm5HTR is expressed in nerve tissue further suggests that serotonin stimulates movement via this receptor by modulating neuronal output to the musculature. Together, the evidence identifies Sm5HTR as an important neuronal protein and a key component of the motor control apparatus in S. mansoni.

Author Summary

The bloodfluke Schistosoma mansoni causes human schistosomiasis, a debilitating disease that afflicts over 200 million people worldwide. There is no vaccine for schistosomiasis, and chemotherapy relies heavily on a single drug, praziquantel. With only one drug available, the prospect of drug resistance is a serious concern, particularly when praziquantel usage is on the rise due to mass treatment programs in many parts of the world. There is a pressing need to identify new drug targets and to develop new chemotherapeutics for schistosomiasis. The focus of this research is on the nervous system of S. mansoni. Many pesticides and antiparasitic drugs act by interacting with neuronal proteins and therefore the nervous system holds great promise for drug discovery. Here we describe a new protein that is present in the nervous system of S. mansoni and regulates movement of the worm. The protein was further identified as a specific receptor for serotonin, an important neurotransmitter and a known modulator of motility in schistosomes. This work shows that the serotonin receptor of S. mansoni is required for proper motor control and therefore is a potential target for chemotherapeutic intervention.