Apela Regulates Fluid Homeostasis by Binding to the APJ Receptor to Activate Gi Signaling
Apela Regulates Fluid Homeostasis by Binding to the APJ Receptor to Activate Gi Signaling
复制标题
Apela 通过与 APJ 受体结合激活 Gi 信号传导来调节体液稳态。
DOI：
10.1074/jbc.m115.648238
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发表时间：
2015-07-24
影响因子：
4.8
通讯作者：
Hsueh, Aaron J. W.
中科院分区：
文献类型：
--
作者：
Deng, Cheng;Chen, Haidi;Hsueh, Aaron J. W.
Apela（APJ早期内源性配体，也称为Apela或toddler）是最近发现的肽类激素。基于对斑马鱼的遗传学研究，发现无肢节在胚胎发育过程中对内胚层分化和心脏发育起重要作用。虽然在胚胎发育过程中apela和APJ缺失斑马鱼的共同表型表明apela与APJ受体相互作用，但apela与APJ结合的动力学和apela的细胞内信号传导途径仍然未知。apela在成人中的作用也不确定。使用嵌合apela配体，我们显示apela以高亲和力（Kd = 0.51 nM）与APJ直接结合，以及apelin（APJ的已知肽配体）竞争apela结合的能力。Apela与apelin相似，通过抑制毛喉素刺激的cAMP产生和诱导ERK 1/2磷酸化，通过抑制性G蛋白途径起作用。在成年大鼠中，apela仅在肾脏中表达，不像apelin的广泛组织分布。体内研究表明，apela能够通过增加利尿和水的摄入量来调节体液平衡。剂量-反应研究进一步表明，apela诱导的最大反应分别比apelin在ERK 1/2磷酸化和利尿/饮水方面高2倍和5倍。在设计apela拮抗剂后，我们进一步证明了内源性配体在调节APJ介导的流体稳态中的作用。我们的研究结果表明，apela作为一种有效的肽激素，能够通过偶联到APJ介导的G（i）信号通路来调节成人肾脏的液体稳态。
Apela ( APJ early endogenous ligand, also known as elabela or toddler) is a recently discovered peptide hormone. Based on genetic studies in zebrafish, apela was found to be important for endoderm differentiation and heart development during embryogenesis. Although common phenotypes of apela and APJ-null zebrafish during embryonic development suggested that apela interacts with the APJ receptor, kinetics of apela binding to APJ and intracellular signaling pathways for apela remain unknown. The role of apela in adults is also uncertain. Using a chimeric apela ligand, we showed direct binding of apela to APJ with high affinity (K-d = 0.51 nM) and the ability of apelin, the known peptide ligand for APJ, to compete for apela binding. Apela, similar to apelin, acts through the inhibitory G protein pathway by inhibiting forskolin-stimulated cAMP production and by inducing ERK1/2 phosphorylation. In adult rats, apela is expressed exclusively in the kidney, unlike the wide tissue distribution of apelin. In vivo studies demonstrated the ability of apela to regulate fluid homeostasis by increasing diuresis and water intake. Dose-response studies further indicated that apela induces 2- and 5-fold higher maximal responses than apelin in ERK1/2 phosphorylation and diuresis/water intake, respectively. After designing an apela antagonist, we further demonstrated the role of endogenous ligand(s) in regulating APJ-mediated fluid homeostasis. Our results identified apela as a potent peptide hormone capable of regulating fluid homeostasis in adult kidney through coupling to the APJ-mediated G(i) signaling pathway.