• Cai Read, Duuamene Nyimanu, Thomas L Williams, David J Huggins, Petra Sulentic, Robyn G C Macrae, Peiran Yang, Robert C Glen, Janet J Maguire, and Anthony P Davenport.
• 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 1; 71 (4): 467-502.

AbstractThe 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 [Pyr1]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.Copyright © 2019 by The Author(s).

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