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 Ca2+ 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.
Highlights
Schistosomiasis, caused by trematode flatworms of the genus Schistosoma, affects hundreds of millions worldwide [1, 2], resulting in chronic morbidity, compromised childhood development, and up to 200,000 deaths annually [3,4,5]
Capsaicin-induced adult hyperactivity exhibits TRPV1-like pharmacology, as it is eliminated by co-exposure to SB 366719, a TRPV1-selective inhibitor. Despite this TRPV1-like pharmacology, we found that adult capsaicin-elicited hyperactivity is eliminated by knockdown of S. mansoni TRPA1-like orthologue (SmTRPA), a S. mansoni TRPA1 orthologue
We previously showed [39] that capsaicin, a potent and selective activator/enhancer of mammalian TRPV1 channels [51], evokes hyperactivity in adult S. mansoni that is dependent on the expression of SmTRPA, a schistosome TRPA1-like gene [39]
Summary
Schistosomiasis, caused by trematode flatworms of the genus Schistosoma, affects hundreds of millions worldwide [1, 2], resulting in chronic morbidity, compromised childhood development, and up to 200,000 deaths annually [3,4,5]. Though the full range of functions fulfilled by TRP channels remains incomplete, it is clear that they play critical roles in responses to all major classes of sensory stimuli, including light, sound, chemicals, temperature, and touch, in large part by regulating intracellular Ca2+ levels [22]. These and the other functions of TRP channels have made them appealing as candidate therapeutic targets [23]. Recent reports indicate that PZQ interacts with mammalian TRP channels [24, 25]
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