Atypical pharmacology of schistosome TRPA1-like ion channels

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.

血吸虫属（Schistosoma）的寄生扁形动物可引发血吸虫病（schistosomiasis）——一种被忽视的热带病，据估算全球范围内有超过2亿人受其侵扰。目前临床仅可使用吡喹酮（Praziquantel）这一种抗血吸虫治疗药物，因此开发新型抗血吸虫疗法的需求极为迫切。离子通道在生理过程中发挥关键调控作用，亦是众多抗蠕虫药物的作用靶点，但截至目前，仅对血吸虫及其他寄生蠕虫中的少数离子通道开展了详细的功能表征。瞬时受体电位（TRP）通道超家族是一类高度多样的非选择性阳离子通道家族，在感觉转导及诸多其他生理功能中扮演核心角色。TRP通道可划分为多个亚家族，其中TRPA与TRPV亚家族成员可在哺乳动物体内转导伤害性与炎症信号，且通常可响应化学刺激与热刺激。此前本团队的研究显示，尽管血吸虫基因组中未预测到可编码TRPV通道的基因，但辣椒素（capsaicin）、树脂毒素（resiniferatoxin）等TRPV1选择性激活剂，可诱导曼氏血吸虫成虫及童虫出现显著的过度活动现象。令人意外的是，这一响应过程依赖于曼氏血吸虫TRPA1同源蛋白（SmTRPA）的表达。本研究证实，在分别表达SmTRPA或埃及血吸虫TRPA1同源蛋白（ShTRPA）的哺乳动物细胞中，辣椒素可引发细胞内钙离子浓度升高。同时，我们还检测了SmTRPA与ShTRPA对多种TRPV1及TRPA1调节剂的响应特性。有趣的是，与SmTRPA不同，ShTRPA无法被TRPA1激活剂异硫氰酸烯丙酯（AITC，allyl isothiocyanate）激活，埃及血吸虫成虫也不会对该化合物产生响应，这一物种差异颇具研究价值。值得关注的是，4-羟基壬烯醛（4-HNE）——一种由宿主产生、可直接激活哺乳动物TRPA1的炎症代谢产物——同样可激活SmTRPA与ShTRPA。本研究结果表明，寄生虫的TRPA1同源通道具有非典型的、兼具TRPA1与TRPV1特性的药理学特征，且可能参与转导内源性宿主信号。