PT  - JOURNAL ARTICLE
AU  - Read, Cai
AU  - Nyimanu, Duuamene
AU  - Williams, Thomas L.
AU  - Huggins, David J.
AU  - Sulentic, Petra
AU  - Macrae, Robyn G. C.
AU  - Yang, Peiran
AU  - Glen, Robert C.
AU  - Maguire, Janet J.
AU  - Davenport, Anthony P.
ED  - Ohlstein, Eliot H.
TI  - International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand
AID  - 10.1124/pr.119.017533
DP  - 2019 Oct 01
TA  - Pharmacological Reviews
PG  - 467--502
VI  - 71
IP  - 4
4099  - http://pharmrev.aspetjournals.org/content/71/4/467.short
4100  - http://pharmrev.aspetjournals.org/content/71/4/467.full
SO  - Pharmacol Rev2019 Oct 01; 71
AB  - 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.