Activation of transient receptor potential channel Sm.(Schistosoma mansoni)TRPM by PZQ, enhanced Ca influx, spastic paralysis, and tegumental disrupture-the deadly cascade in parasitic schistosomes, other trematodes, and cestodes.

After almost 50 years of praziquantel (PZQ) research, Park and Marchant (Trends Parasitol 36:182-194, 2020) described the Ca-permeable transient receptor potential (TRP) channel Sm.TRPM in Schistosoma mansoni as target of PZQ. Here we describe the deadly cascade in schistosomes which is induced by the (R)-PZQ enantiomer that includes contemporaneous stereoselective activation of Sm.TRPM-mediated Ca influx, disturbed Ca homeostasis, Ca-dependent spastic paralysis, and Ca- and PZQ-dependent disruption of parasitic teguments. Under normal conditions, there is a reversible balance between bilayer, isotropic, and HII phases in biological membranes (Jouhet 2013). In vitro, we could observe an irreversible but not stereoselective transition to the HII phase in liposomes consisting of phosphatidylethanolamine (PE) and phosphatidylserine (PS), two naturally occurring phospholipids in schistosomes, by the concerted action of Ca and PZQ (Harder 2013). HII structures are a prerequisite for induction of fusion processes (Jouhet 2013), which, indeed, become visible as blebs, vacuolation processes, and large balloon-like surface exudates in a large variety of PZQ-sensitive parasitic flukes and cestodes after PZQ treatment. These tegument damages are irreversible. As homologs of Sm.TRPM are also present in the other trematodes S. japonicum, S. haematobium, or Clonorchis sinensis and cestodes Taenia solium, Echinococcus multilocularis, or Hymenolepis microstoma (Park and Marchant, Trends Parasitol 36:182-194, 2020), it is suggested that a similar deadly cascade will be operating generally in PZQ-sensitive parasites.