FMRFamide-like peptides (FLPs) enhance voltage-gated calcium currents to elicit muscle contraction in the human parasite Schistosoma mansoni.
FMRFamide-like peptides (FLPs) enhance voltage-gated calcium currents to elicit muscle contraction in the human parasite Schistosoma mansoni.
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DOI：
10.1371/journal.pntd.0000790
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发表时间：
2010-08-10
影响因子：
3.8
通讯作者：
Day TA
中科院分区：
文献类型：
--
作者：
Novozhilova E;Kimber MJ;Qian H;McVeigh P;Robertson AP;Zamanian M;Maule AG;Day TA
血吸虫是世界上最重要和最被忽视的病原体之一，血吸虫病的控制几乎完全依赖于一种药物。血吸虫的神经肌肉系统是治疗干预的肥沃土壤，但涉及神经肌肉功能的生理事件的细节在很大程度上仍不清楚。短酰胺化神经肽，即FMRFamide样肽，广泛分布于所有被研究的扁虫的神经系统中，并产生强大的肌肉兴奋作用。我们的目标是确定FLPs引起血吸虫肌肉纤维收缩的机制。收缩研究表明，FLP Tyr-Ile-Arg-Phe-amide(YIRFamide)收缩肌肉纤维的机制需要通过肌膜电压操作的钙通道(VOCC)内流，而经典的VOCC阻滞剂尼卡地平、维拉帕米和甲氧维拉帕米可以抑制这种收缩。全细胞膜片钳实验显示，施加1µM YIRFamide可显著且可逆地增强VOCC的内向电流，持续内向电流增加到对照组的190%，峰值电流增加到180%。为了研究FLP受体与VOCCs之间的生化联系，我们测试了PKC抑制剂Calphostin C、RO31-8220和白屈菜红碱，它们都能浓度依赖性地阻断1µM YIRFamide引起的收缩。综上所述，这些数据表明，FLPs通过依赖PKC的途径，通过VOCC电流促进钙离子内流，从而引起收缩。血吸虫病是由血吸虫属吸虫感染引起的。这种疾病困扰着2亿多人，大部分疾病负担集中在世界上一些最贫穷的国家。血吸虫病的控制在很大程度上取决于单一药物吡喹酮的化疗，这种不稳定的情况要求发现和开发新的抗血吸虫药物。发现新药的一个障碍是对这些寄生虫的一些基本生物学过程缺乏了解。在这里，我们朝着阐明血吸虫神经肌肉控制的信号和通路迈出了重要的一步，血吸虫神经肌肉控制是一种被证明易受化疗干预的中心生物学功能。已知神经肽在扁虫肌肉控制中起重要作用，在这里我们发现FMRFamide样肽通过电压操纵的钙通道促进钙内流来收缩血吸虫肌肉。我们还发现，肌肉兴奋性神经肽的受体使用蛋白激酶C途径来刺激电压操作的钙通道。了解这些蠕虫神经肌肉生理学中涉及的分子有助于确定新一代抗血吸虫药物的潜在有用靶点。
Schistosomes are amongst the most important and neglected pathogens in the world, and schistosomiasis control relies almost exclusively on a single drug. The neuromuscular system of schistosomes is fertile ground for therapeutic intervention, yet the details of physiological events involved in neuromuscular function remain largely unknown. Short amidated neuropeptides, FMRFamide-like peptides (FLPs), are distributed abundantly throughout the nervous system of every flatworm examined and they produce potent myoexcitation. Our goal here was to determine the mechanism by which FLPs elicit contractions of schistosome muscle fibers. Contraction studies showed that the FLP Tyr-Ile-Arg-Phe-amide (YIRFamide) contracts the muscle fibers through a mechanism that requires Ca2+ influx through sarcolemmal voltage operated Ca2+ channels (VOCCs), as the contractions are inhibited by classical VOCC blockers nicardipine, verapamil and methoxyverapamil. Whole-cell patch-clamp experiments revealed that inward currents through VOCCs are significantly and reversibly enhanced by the application of 1 µM YIRFamide; the sustained inward currents were increased to 190% of controls and the peak currents were increased to 180%. In order to examine the biochemical link between the FLP receptor and the VOCCs, PKC inhibitors calphostin C, RO 31–8220 and chelerythrine were tested and all produced concentration dependent block of the contractions elicited by 1 µM YIRFamide. Taken together, the data show that FLPs elicit contractions by enhancing Ca2+ influx through VOCC currents using a PKC-dependent pathway. Schistosomiasis (bilharzia) is caused by infection with trematodes of the genus Schistosoma. The disease afflicts over 200 million people, with the bulk of the disease burden focused in some of the world's poorest countries. Schistosomiasis control rests largely on chemotherapy with a single drug, praziquantel, a precarious situation calling for the discovery and development of new antischistosomal agents. One hindrance to the discovery of new drugs is a deficiency of knowledge regarding some basic biological processes of these parasitic worms. Here, we take significant steps toward the elucidation of signaling and pathways involved in schistosome neuromuscular control, a central biological function with proven vulnerability to chemotherapeutic intervention. Neuropeptides are known to be important in flatworm muscle control and here we find that FMRFamide-like peptides act to contract schistosome muscle by enhancing calcium influx through voltage-operated calcium channels. We also found that the receptor for the myoexcitatory neuropeptides uses a protein kinase C pathway to stimulate the voltage-operated calcium channels. Understanding the molecules involved in the neuromuscular physiology of these worms helps to identify potentially useful targets for a new generation of antischistosomal drugs.
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影响因子：
4
作者：
Jeziorski, Michael C.;Greenberg, Robert M.
通讯作者：
Greenberg, Robert M.
影响因子：
2.4
作者：
Mendonca-Silva, D. L.;Novozhilova, E.;Day, T. A.
通讯作者：
Day, T. A.
DOI：
10.1016/0006-291x(90)91544-3
发表时间：
1990-11-15
影响因子：
3.1
作者：
HERBERT, JM;AUGEREAU, JM;MAFFRAND, JP
通讯作者：
MAFFRAND, JP
影响因子：
2.4
作者：
DAY, TA;BENNETT, JL;PAX, RA
通讯作者：
PAX, RA
影响因子：
2.1
作者：
BLAIR, KL;BENNETT, JL;PAX, RA
通讯作者：
PAX, RA