BACKGROUND The neuropeptide Y system affects various processes, among others food intake, and is frequently discussed in the context of targeting obesity. Studies in model organisms are indispensable to enable molecular studies in a physiological context. Although the NPY system is evolutionarily conserved in all bilaterians, in the widely used model Caenorhabditis elegans there is controversy on the existence of NPY orthologous molecules. While the FMRFamide-like peptide (FLP)/Neuropeptide receptor-Resemblance (NPR) system in the nematode was initially suggested to be orthologous to the mammalian NPY system, later global phylogenetic studies indicate that FLP/NPR is protostome-specific. METHODS We performed a comprehensive pharmacological study of the FLP/NPR system in transfected cells in vitro, and tested for functional substitution in C. elegans knockout strains. Further, we phenotypically compared different flp loss-of-function strains. Differences between groups were compared by ANOVA and post-hoc testing (Dunnett, Bonferroni). RESULTS Our pharmacological analysis of the FLP/NPR system including formerly functionally uncharacterized NPY-like peptides from C. elegans demonstrates that G protein-coupling and ligand requirements for receptor activation are similar to the human NPY system. In vitro and in vivo analyses show cross-reactivity of NPY with the FLP/NPR system manifesting in the ability of the human GPCRs to functionally substitute FLP/NPR signaling in vivo. The high pharmacological/functional similarities enabled us to identify C. elegans FLP-14 as a key molecule in avoidance behavior. CONCLUSIONS Our data demonstrate the pharmacological and functional similarities of human NPY and C. elegans NPR systems. This adds a novel perspective to current phylogenetic reconstructions of the neuropeptide Y system. NPY and NPR receptors are pharmacologically so similar that the human receptors can functionally compensate for the C. elegans ones, suggesting orthologous relationships. This is also underlined by the presence of NPY-like peptides and parallels in peptide requirements for receptor activation. Further, the results presented here highlight the potential of this knowledge for physiological as well as molecular studies on neuropeptide GPCRs such as the NPY system in the future.

中文翻译：

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秀丽隐杆线虫中人神经肽Y系统的药理和功能相似性挑战了FLP / NPR系统的系统发育观点。

背景技术神经肽Y系统影响各种过程，尤其是食物摄入，并且在针对肥胖症的背景下经常讨论。对模型生物的研究对于在生理背景下进行分子研究是必不可少的。尽管NPY系统在所有双语者中在进化上都是保守的，但在广泛使用的秀丽隐杆线虫模型中，存在关于NPY直系同源分子的争议。虽然最初建议线虫中的FMRFamide样肽（FLP）/神经肽受体类似物（NPR）系统与哺乳动物NPY系统同源，但后来的全球系统发育研究表明FLP / NPR是原生动物特异性的。方法我们在体外转染细胞中对FLP / NPR系统进行了全面的药理研究，并测试了C中的功能取代。线虫敲除菌株。此外，我们在表型上比较了不同的flp功能丧失菌株。通过方差分析和事后检验（Dunnett，Bonferroni）比较了两组之间的差异。结果我们对FLP / NPR系统的药理学分析包括以前从秀丽隐杆线虫获得的功能上未表征的NPY样肽，表明受体激活的G蛋白偶联和配体需求与人NPY系统相似。体外和体内分析显示NPY与FLP / NPR系统的交叉反应性表现为人GPCR在体内功能性替代FLP / NPR信号传导的能力。高度的药理学/功能相似性使我们能够将秀丽隐杆线虫FLP-14鉴定为逃避行为的关键分子。结论我们的数据证明了人NPY和秀丽隐杆线虫NPR系统的药理和功能相似性。这为神经肽Y系统的当前系统发育重建增添了新的视角。NPY和NPR受体在药理学上是如此相似，以至于人类受体可以在功能上补偿秀丽隐杆线虫的受体，提示直系同源关系。NPY样肽的存在和受体激活所需肽中的类似物也突显了这一点。此外，这里提出的结果突出了该知识在未来对神经肽GPCR（例如NPY系统）的生理学和分子研究中的潜力。NPY和NPR受体在药理学上是如此相似，以至于人类受体可以在功能上补偿秀丽隐杆线虫的受体，提示直系同源关系。NPY样肽的存在和受体激活所需肽中的类似物也突显了这一点。此外，这里提出的结果突出了该知识在未来对神经肽GPCR（例如NPY系统）的生理学和分子研究中的潜力。NPY和NPR受体在药理学上是如此相似，以至于人类受体可以在功能上补偿秀丽隐杆线虫的受体，提示直系同源关系。NPY样肽的存在和受体激活所需肽中的类似物也突显了这一点。此外，这里提出的结果突出了该知识在未来对神经肽GPCR（例如NPY系统）的生理学和分子研究中的潜力。