The orphan G protein-coupled receptor 25 (GPR25) is activated by Apelin and Apela in non-mammalian vertebrates.
The orphan G protein-coupled receptor 25 (GPR25) is activated by Apelin and Apela in non-mammalian vertebrates.
复制标题
DOI：
10.1016/j.bbrc.2018.04.229
复制
发表时间：
2018-06
影响因子：
3.1
通讯作者：
Jiannan Zhang (张剑南);Y. Wan;C. Fang;Junan Chen;Wangan Ouyang;Juan Li;Yajun Wang
中科院分区：
文献类型：
--
作者：
Jiannan Zhang (张剑南);Y. Wan;C. Fang;Junan Chen;Wangan Ouyang;Juan Li;Yajun Wang
G蛋白偶联受体25 （GPR25）是脊椎动物中一种孤立的G蛋白偶联受体，已被认为与自身免疫性疾病和调节人类血压有关。然而，在脊椎动物中，GPR25的内源性配体仍然未知。在非哺乳动物脊椎动物（斑马鱼、斑点鱼和鸽子）中，GPR25可以被Apelin和Apela肽激活，这两种肽也是脊椎动物Apelin受体（APLNR）的两种内源性配体。通过pgl3 - cre -荧光素酶报告基因检测和共聚焦显微镜，我们首次证明了斑马鱼HEK293 细胞中表达的GPR25与APLNR一样，可以被斑马鱼Apelin和Apela肽有效激活，从而抑制福斯克林刺激的cAMP产生和受体内化。与斑马鱼的GPR25一样，鸽子和斑gar的GPR25也可以被Apelin和Apela激活，并且它们的激活可以抑制forskolin诱导的cAMP积累。有趣的是，与斑马鱼（/斑鱼/鸽子）的GPR25不同，在相同的实验条件下，人的GPR25不能被Apelin和Apela激活。RNA-seq分析进一步揭示了GPR25在多种组织中表达，包括斑马鱼/斑马鱼/人类的睾丸和肠道，这意味着GPR25信号在脊椎动物的许多生理过程中可能发挥作用。综上所述，我们的数据不仅首次证明了孤儿受体GPR25具有两种潜在的配体Apelin和Apela，其激活降低了非哺乳动物脊椎动物细胞内cAMP水平，而且有助于揭示GPR25信号传导在脊椎动物中的生理作用。
G protein-coupled receptor 25 (GPR25) is an orphan G protein-coupled receptor in vertebrates, that has been implicated to be associated with autoimmune diseases and regulate blood pressure in humans. However, the endogenous ligand of GPR25 remains unknown in vertebrates. Here, we reported that in non-mammalian vertebrates (zebrafish, spotted gars, and pigeons), GPR25 could be activated by Apelin and Apela peptides, which are also the two endogenous ligands of vertebrate Apelin receptor (APLNR). Using the pGL3-CRE-luciferase reporter assay and confocal microscopy, we first demonstrated that like APLNR, zebrafish GPR25 expressing in HEK293 cells could be effectively activated by zebrafish Apelin and Apela peptides, leading to the inhibition of forskolin-stimulated cAMP production and receptor internalization. Like zebrafish GPR25, pigeon and spotted gar GPR25 could also be activated by Apelin and Apela, and their activation could inhibit forskolin-induced cAMP accumulation. Interestingly, unlike zebrafish (/spotted gar/pigeon) GPR25, human GPR25 could not be activated by Apelin and Apela under the same experimental conditions. RNA-seq analysis further revealed thatGPR25is expressed in a variety of tissues, including the testes and intestine of zebrafish/spotted gars/humans, implying the potential roles of GPR25 signaling in many physiological processes in vertebrates. Taken together, our data not only provides the first proof that the orphan receptor GPR25 possesses two potential ligands ‘Apelin and Apela’ and its activation decreases intracellular cAMP levels in non-mammalian vertebrates, but also facilitates to unravel the physiological roles of GPR25 signaling in vertebrates.