Abstract
Ion channels have proved to be productive targets for anthelmintic chemotherapy. One example is the recent discovery of a parasitic flatworm ion channel targeted by praziquantel (PZQ), the main clinical therapy used for treatment of schistosomiasis. The ion channel activated by PZQ - a transient receptor potential ion channel of the melastatin subfamily, named TRPM(PZQ) - is a Ca(2+)-permeable ion channel expressed in all parasitic flatworms that are PZQ-sensitive. However, little is currently known about the electrophysiological properties of this target that mediates the deleterious action of PZQ on many trematodes and cestodes. Here, we provide a detailed biophysical characterization of the properties of Schistosoma mansoni TRPM(PZQ) channel (Sm.TRPM(PZQ)) in response to PZQ. Single channel electrophysiological analysis demonstrated that Sm.TRPM(PZQ) when activated by PZQ is a non-selective, large conductance, voltage-insensitive cation channel that displays distinct properties from human TRPM paralogs. Sm.TRPM(PZQ) is Ca(2+)-permeable but does not require Ca(2+) for channel gating in response to PZQ. TRPM(PZQ) from Schistosoma japonicum (Sj.TRPM(PZQ)) and Schistosoma haematobium (Sh.TRPM(PZQ)) displayed similar characteristics. Profiling Sm.TRPM(PZQ) responsiveness to PZQ has established a biophysical signature for this channel that will aid future investigation of endogenous TRPM(PZQ) activity, as well as analyses of endogenous and exogenous regulators of this novel, druggable antiparasitic target.