Atypical TRP Channel Pharmacology in Schistosomes

Abstract

Parasitic flatworms of the genus Schistosoma cause schistosomiasis, a neglected tropical disease affecting over 200 million people. Only one drug is available for treatment and control, and there is an urgent need for new or repurposed antischistosomal agents. Ion channels are validated targets for current anthelmintics, but the roles and pharmacological sensitivities of transient receptor potential (TRP) channels are essentially unexplored in schistosomes and other parasitic helminths. We are using TRP channel modulators, RNA interference, and heterologous expression to examine the function and pharmacology of TRP channels in schistosomes. Though the S. mansoni genome predicts representatives of most TRP channel subfamilies, TRPV channels are notably absent. Despite this lack of TRPV-like channels, both adult and larval schistosomes exhibit dramatic hyperactivity in response to selective activators of mammalian TRPV1 such as capsaicin and resiniferatoxin. Capsaicin also causes rapid separation of paired adult males and females, perhaps indicative of a nociceptive response. The response to capsaicin is blocked by selective TRPV1 antagonists, further evidence for TRPV1-like pharmacology. Surprisingly, the capsaicin-induced hyperactivity in adult worms is virtually eliminated by knockdown of SmTRPA, a schistosome TRPA1-like channel. The TRPA1 activator AITC also elicits significant hyperactivity that is abolished by knockdown of SmTRPA1, indicating that SmTRPA exhibits mixed TRPV1/TRPA1-like pharmacology. Consistent with this hypothesis, exposure of SmTRPA-expressing mammalian cells to capsaicin or AITC elicits an influx of calcium, as measured by Fura-2 ratiometric imaging. These results suggest that some TRPV1-mediated sensory functions may be fulfilled by schistosome TRP channels from other subfamilies, and that at least one schistosome TRP channel has atypical pharmacological sensitivities that could be selectively targeted for development of new antischistosomal therapeutics. Other schistosome TRP channels might also be exploitable for targeting.