Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, United Kingdom (C.R., D.N., T.L.W., D.J.H., P.S., R.G.C.M., P.Y., J.J.M., A.P.D.); The Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom (D.J.H., R.C.G.); and Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom (R.C.G.).
Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, United Kingdom (C.R., D.N., T.L.W., D.J.H., P.S., R.G.C.M., P.Y., J.J.M., A.P.D.); The Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom (D.J.H., R.C.G.); and Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom (R.C.G.)
Pharmacol Rev. 2019 Oct;71(4):467-502. doi: 10.1124/pr.119.017533.
The predicted protein encoded by the APJ gene discovered in 1993 was originally classified as a class A G protein-coupled orphan receptor but was subsequently paired with a novel peptide ligand, apelin-36 in 1998. Substantial research identified a family of shorter peptides activating the apelin receptor, including apelin-17, apelin-13, and [Pyr]apelin-13, with the latter peptide predominating in human plasma and cardiovascular system. A range of pharmacological tools have been developed, including radiolabeled ligands, analogs with improved plasma stability, peptides, and small molecules including biased agonists and antagonists, leading to the recommendation that the APJ gene be renamed APLNR and encode the apelin receptor protein. Recently, a second endogenous ligand has been identified and called Elabela/Toddler, a 54-amino acid peptide originally identified in the genomes of fish and humans but misclassified as noncoding. This precursor is also able to be cleaved to shorter sequences (32, 21, and 11 amino acids), and all are able to activate the apelin receptor and are blocked by apelin receptor antagonists. This review summarizes the pharmacology of these ligands and the apelin receptor, highlights the emerging physiologic and pathophysiological roles in a number of diseases, and recommends that Elabela/Toddler is a second endogenous peptide ligand of the apelin receptor protein.
1993 年发现的 APJ 基因编码的预测蛋白最初被归类为 A 类 G 蛋白偶联孤儿受体，但随后在 1998 年与一种新型肽配体——apelin-36 配对。大量研究确定了一系列激活 apelin 受体的较短肽，包括 apelin-17、apelin-13 和 [Pyr]apelin-13，其中后一种肽在人血浆和心血管系统中占优势。已经开发出一系列药理学工具，包括放射性标记配体、血浆稳定性提高的类似物、肽和小分子，包括偏向激动剂和拮抗剂，因此建议将 APJ 基因重新命名为 APLNR，并编码 apelin 受体蛋白。最近，已经鉴定出第二种内源性配体，并将其命名为 Elabela/Toddler，这是一种 54 个氨基酸的肽，最初在鱼类和人类基因组中被发现，但被错误归类为非编码。这种前体也能够被切割成较短的序列（32、21 和 11 个氨基酸），所有这些都能够激活 apelin 受体，并被 apelin 受体拮抗剂阻断。本文综述了这些配体和 apelin 受体的药理学，强调了它们在多种疾病中的新兴生理和病理生理作用，并建议 Elabela/Toddler 是 apelin 受体蛋白的第二种内源性肽配体。
Zotero 插件
