Discussion

Schistosomiasis is a parasitic flatworm infection that afflicts over 200 million people worldwide. The drug praziquantel (PZQ) remains the key clinical therapy to treat schistosomiasis and has been used for several decades. PZQ is also used to treat other diseases caused by parasitic flatworms. The clinical formulation of PZQ is a racemate (±PZQ) composed of the enantiomers (R)-PZQ and (S)-PZQ. (R)-PZQ causes Ca²⁺ influx, spastic paralysis and tegumental damage of adult schistosomes – however the molecular targets that mediate these effects in the worm remain unknown. Here, we have identified a Ca²⁺-permeable ion channel that is activated by (R)-PZQ in the nanomolar range. This channel, christened Sm.TRPM_PZQ, is a member of the transient receptor potential melastatin (TRPM) channel subfamily. In heterologous expression assays, PZQ caused a long-lasting activation of Sm.TRPM_PZQ in the absence of clear desensitization. Concentration response analysis revealed that (R)-PZQ activated Sm.TRPM_PZQ with an EC₅₀ of 597±10nM in Ca²⁺ imaging analysis and this activation was stereoselective, with the (R)-PZQ evoking Ca²⁺ signals over a considerably lower concentration range than (S)-PZQ (EC₅₀ of 27.9±3.1µM). Sm.TRPM_PZQ was expressed across various schistosome life cycle stages and was also present in other free-living and parasitic flatworms that exhibit sensitivity to PZQ. These data provide the first report of a schistosome target activated by PZQ and are consistent with Sm.TRPM_PZQ being a target of this clinically important therapeutic.