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Abstract
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 [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.
Highlights
The predicted protein encoded by the APJ gene was discovered by O’Dowd et al (1993) and was originally classified as a class A G protein-coupled orphan receptor but was subsequently paired with a novel peptide ligand, apelin 36 (APJ endogenous ligand) discovered by Tatemoto et al (1998)
Novel ligands based on ELA structure-activity are beginning to be discovered, and these may enable the action of the two endogenous pathways at the same receptor to be dissected (Murza et al, 2016)
The apelin receptor has been shown to be tractable to discovering both peptide and small molecule ligands biased toward activating the G protein pathway to cause the desired vasodilatation and increase in cardiac output without desensitizing the receptor
Summary
The predicted protein encoded by the APJ gene was discovered by O’Dowd et al (1993) and was originally classified as a class A G protein-coupled orphan receptor but was subsequently paired with a novel peptide ligand, apelin 36 (APJ endogenous ligand) discovered by Tatemoto et al (1998). It shows little sequence homology to apelin with only about 25% conservation (Xie et al, 2014), there is some similarity in the location of hydrophobic residues The discovery of this new ligand opens up a number of exciting possibilities. This review will discuss the structure and signaling pathways of the apelin receptor and its endogenous ligands, apelin and ELA, before moving on to the development of synthetic agonists and antagonists It will discuss some of the roles that apelin and ELA have been shown to play in both physiologic and pathophysiological conditions, highlighting the importance of the two ligands and the therapeutic potential of targeting the apelin system. The following reviews focus on the apelin signaling pathway in disease: cardiovascular, Scimia et al (2014), Dalzell et al (2015), Kuba et al (2019); myocardial ischemia and reperfusion injury, Chen et al (2016); vascular smooth muscle, Luo et al (2018); endothelial cell dysfunction, Cheng et al (2019); pulmonary hypertension, Kim (2014); hypertension, Gilbert (2017); stroke Wu et al (2017b); renal, Huang et al (2018); liver, Lv et al (2017); cancer, Yang et al (2016); diabetes and metabolic diseases CastanLaurell et al (2012, 2019), Bertrand et al (2015), Chaves-Almagro et al, (2015), Hu et al, (2016), Alipour et al, (2017)
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