Ubuka Takayoshi, Tsutsui Kazuyoshi
Laboratory of Integrative Brain Sciences, Department of Biology and Center for Medical Life Science, Waseda University, Shinjuku, Japan.
Front Neurosci. 2018 Oct 18;12:747. doi: 10.3389/fnins.2018.00747. eCollection 2018.
Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that was found in the brain of Japanese quail when investigating the existence of RFamide peptides in birds. GnIH was named because it decreased gonadotropin release from cultured anterior pituitary, which was located in the hypothalamo-hypophysial system. GnIH and GnIH precursor gene related peptides have a characteristic C-terminal LPXRFamide (X = L or Q) motif that is conserved in jawed vertebrates. Orthologous peptides to GnIH are also named RFamide related peptide or LPXRFamide peptide from their structure. A G-protein coupled receptor GPR147 is the primary receptor for GnIH. Similarity-based clustering of neuropeptide precursors in metazoan species indicates that GnIH precursor of vertebrates is evolutionarily related to FMRFamide precursor of mollusk and nematode. FMRFamide peptide is the first RFamide peptide that was identified from the ganglia of the venus clam. In order to infer the evolutionary history of the GnIH-GnIH receptor system we investigate the structural similarities between GnIH and its receptor and well-studied nematode () FMRFamide-like peptides (FLPs) and their receptors. We also compare the functions of FLPs of nematode with GnIH of chordates. A multiple sequence alignment and phylogenetic analyses of GnIH, neuropeptide FF (NPFF), a paralogous peptide of GnIH, and FLP precursors have shown that GnIH and NPFF precursors belong to different clades and some FLP precursors have structural similarities to either precursor. The peptide coding regions of FLP precursors in the same clade align well with those of GnIH or NPFF precursors. Alignment of GnIH (LPXRFa) peptides of chordates and FLPs of grouped the peptides into five groups according to the last C-terminal amino acid sequences, which were MRFa, LRFa, VRFa, IRFa, and PQRFa. Phylogenetic analysis of receptors suggested that GPR147 has evolutionary relationships with FLP receptors, which regulate reproduction, aggression, locomotion, and feeding. GnIH and some FLPs mediate the effect of stress on reproduction and behavior, which may also be a conserved property of these peptide systems. Future studies are needed to investigate the mechanism of how neuropeptide precursor genes are mutated to evolve new neuropeptides and their inheritance.
促性腺激素抑制激素（GnIH）是一种下丘脑神经肽，在研究鸟类中RFamide肽的存在时，在日本鹌鹑的大脑中被发现。GnIH之所以得名，是因为它能减少来自位于下丘脑 - 垂体系统中的培养垂体前叶的促性腺激素释放。GnIH及其前体基因相关肽具有特征性的C末端LPXRFamide（X = L或Q）基序，该基序在有颌脊椎动物中保守。与GnIH直系同源的肽也因其结构而被命名为RFamide相关肽或LPXRFamide肽。G蛋白偶联受体GPR147是GnIH的主要受体。后生动物物种中基于相似性的神经肽前体聚类表明，脊椎动物的GnIH前体在进化上与软体动物和线虫的FMRFamide前体相关。FMRFamide肽是从金星蛤神经节中鉴定出的首个RFamide肽。为了推断GnIH - GnIH受体系统的进化历史，我们研究了GnIH与其受体以及已深入研究的线虫的FMRFamide样肽（FLP）及其受体之间的结构相似性。我们还比较了线虫FLP与脊索动物GnIH的功能。对GnIH、神经肽FF（NPFF，GnIH的旁系同源肽）和FLP前体的多序列比对和系统发育分析表明，GnIH和NPFF前体属于不同的进化枝，一些FLP前体与其中任何一种前体具有结构相似性。同一进化枝中FLP前体的肽编码区与GnIH或NPFF前体的肽编码区排列良好。根据脊索动物的GnIH（LPXRFa）肽和线虫的FLP的C末端最后氨基酸序列，将这些肽分为五组，即MRFa、LRFa、VRFa、IRFa和PQRFa。受体的系统发育分析表明，GPR147与调节生殖、攻击、运动和摄食的FLP受体具有进化关系。GnIH和一些FLP介导应激对生殖和行为的影响，这也可能是这些肽系统的保守特性。未来需要研究神经肽前体基因如何突变以进化出新的神经肽及其遗传机制。
