Atypical pharmacology of schistosome TRPA1-like ion channels

Abstract

Parasitic flatworms of the genus Schistosoma cause schistosomiasis, a neglected tropical disease estimated to affect over 200 million people worldwide. Praziquantel is the only antischistosomal currently available for treatment, and there is an urgent need for new therapeutics. Ion channels play key roles in physiology and are targets for many anthelmintics, yet only a few representatives have been characterized in any detail in schistosomes and other parasitic helminths. The transient receptor potential (TRP) channel superfamily comprises a diverse family of non-selective cation channels that play key roles in sensory transduction and a wide range of other functions. TRP channels fall into several subfamilies. Members of both the TRPA and TRPV subfamilies transduce nociceptive and inflammatory signals in mammals, and often also respond to chemical and thermal signals. We previously showed that although schistosomes contain no genes predicted to encode TRPV channels, TRPV1-selective activators such as capsaicin and resiniferatoxin elicit dramatic hyperactivity in adult worms and schistosomula. Surprisingly, this response requires expression of a S. mansoni TRPA1-like orthologue (SmTRPA). Here, we show that capsaicin induces a rise in intracellular Ca ²⁺ in mammalian cells expressing either SmTRPA or a S. haematobium TRPA1 orthologue (ShTRPA). We also test SmTRPA and ShTRPA responses to various TRPV1 and TRPA1 modulators. Interestingly, in contrast to SmTRPA, ShTRPA is not activated by the TRPA1 activator AITC (allyl isothiocyanate), nor do S. haematobium adult worms respond to this compound, a potentially intriguing species difference. Notably, 4-hydroxynonenal (4-HNE), a host-derived, inflammatory product that directly activates mammalian TRPA1, also activates both SmTRPA and ShTRPA. Our results point to parasite TRPA1-like channels which exhibit atypical, mixed TRPA1/TRPV1-like pharmacology, and which may also function to transduce endogenous host signals.

Author summary

Schistosomes are parasitic flatworms that infect hundreds of millions of people worldwide. They cause schistosomiasis, a disease with major consequences for human health and economic development. There is only a single drug available for treatment and control of this highly prevalent disease, and there is an urgent need for development of new treatments. TRP ion channels play key roles in sensory (and other) functions. One type of TRP channel, TRPV1, is activated by capsaicin, the active ingredient in hot peppers. However, schistosomes do not have any TRPV-like channels. Nonetheless, we previously showed that capsaicin and similar compounds induce dramatic hyperactivity in schistosomes, and that this response is abolished by suppressing expression of SmTRPA, a schistosome TRPA1-like channel. Mammalian TRPA1 channels are not sensitive to capsaicin. Here, we show that the SmTRPA channel itself responds to capsaicin, resulting in an influx of Ca ²⁺ into cells. ShTRPA, a TRPA1-like channel from another schistosome, S. haematobium, is also sensitive to capsaicin. Thus, the pharmacology of schistosome TRPA1 channels apparently differs from that of host mammalian channels, a characteristic that could indicate mixed TRPA/TRPV functionality and might be exploitable for development of new antischistosomal drugs. Furthermore, we show that schistosome TRPA1-like channels are activated by host-derived compounds, perhaps indicating a mechanism by which the parasite can respond to host signals.