Large-Scale Combinatorial Deorphanization of Platynereis Neuropeptide GPCRs
Large-Scale Combinatorial Deorphanization of Platynereis Neuropeptide GPCRs
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DOI：
10.1016/j.celrep.2015.06.052
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发表时间：
2015-07-28
期刊：
影响因子：
8.8
通讯作者：
Jekely, Gaspar
中科院分区：
文献类型：
--
作者：
Bauknecht, Philipp;Jekely, Gaspar
神经肽是一类最大的神经调节剂，通常由g蛋白偶联受体（gpcr）发出信号。虽然一些后生动物的神经肽库已经被表征，但许多gpcr是孤儿。在这里，我们开发了一种策略来识别gpcr -肽对使用组合筛选与复杂的肽混合物。我们筛选了126种针对鸭嘴兽87种gpcr的神经肽，并鉴定了19种受体的配体。我们将许多gpcr分配到已知的家族，并确定了achatin， FMRFamide, RGWamide， FLamide和11in受体的保守家族。我们还鉴定了一种脊椎动物促甲状腺激素释放激素（TRH）受体的Platynereis同源配体，揭示了TRH受体信号传导的古老起源。我们预测了几种后生动物gpcr的配体，并测试了预测的achatin受体。这些受体被一种achatin d肽特异性激活，揭示了一种保守的激活模式。我们的工作建立了一个重要的资源，并提供了关于多肽能信号传导的复杂性的信息。
Neuropeptides, representing the largest class of neuromodulators, commonly signal by G-protein-coupled receptors (GPCRs). While the neuropeptide repertoire of several metazoans has been characterized, many GPCRs are orphans. Here, we develop a strategy to identify GPCR-peptide pairs using combinatorial screening with complex peptide mixtures. We screened 126 neuropeptides against 87 GPCRs of the annelid Platynereis and identified ligands for 19 receptors. We assigned many GPCRs to known families and identified conserved families of achatin, FMRFamide, RGWamide, FLamide, and elevenin receptors. We also identified a ligand for the Platynereis ortholog of vertebrate thyrotropin-releasing hormone (TRH) receptors, revealing the ancient origin of TRH-receptor signaling. We predicted ligands for several metazoan GPCRs and tested predicted achatin receptors. These receptors were specifically activated by an achatin D-peptide, revealing a conserved mode of activation. Our work establishes an important resource and provides information about the complexity of peptidergic signaling in the urbilaterian.