Atypical pharmacology of schistosome TRPA1-like ion channels
Atypical pharmacology of schistosome TRPA1-like ion channels
复制标题
DOI：
10.1371/journal.pntd.0006495
复制
发表时间：
2018-05-01
影响因子：
3.8
通讯作者：
Greenberg, Robert M.
中科院分区：
文献类型：
--
作者：
Bais, Swarna;Berry, Corbett T.;Greenberg, Robert M.
血吸虫属的寄生扁虫会导致血吸虫病，这是一种被忽视的热带疾病，估计影响全球超过2亿人。吡喹酮是目前唯一可用于治疗的抗组胺药，迫切需要新的治疗方法。离子通道在生理学中起着关键作用，是许多驱虫药的靶标，但在寄生虫和其他寄生蠕虫中，只有少数代表被详细描述。瞬时受体电位（TRP）通道超家族包括在感觉传导和广泛的其他功能中起关键作用的非选择性阳离子通道的多样性家族。TRP通道分为几个亚家族。TRPA和TRPV亚家族的成员在哺乳动物中产生伤害性和炎症信号，并且通常也对化学和热信号作出反应。我们以前表明，虽然不含预测编码TRPV通道的基因，TRPV 1选择性激活剂，如辣椒素和树脂毒素引起显着的过度活跃，在蠕虫和童虫。令人惊讶的是，这种反应需要表达S。mansoni TRPA-1样直向同源物（SmTRPA）。在这里，我们发现辣椒素诱导表达SmTRPA或S.血红蛋白TRPA 1直系同源物（ShTRPA）。我们还测试了SmTRPA和ShTRPA对各种TRPV 1和TRPA 1调节剂的反应。有趣的是，与SmTRPA相反，ShTRPA不被TRPA 1激活剂AITC（异硫氰酸烯丙酯）激活，S也不被激活。埃及血蜱蠕虫对这种化合物有反应，这是一种潜在的有趣的物种差异。值得注意的是，4-羟基壬烯醛（4-HNE），一种直接激活哺乳动物TRPA 1的宿主衍生的炎症产物，也激活SmTRPA和ShTRPA。我们的研究结果表明，寄生虫TRPA 1样通道表现出非典型的，混合TRPA 1/TRPV 1样药理学，也可能起到抑制内源性宿主信号的作用。
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 TRPA-1-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.