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

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 [Pyr 1 ]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 54amino 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. 468 Read et al. Receptor residues implicated in apelin binding by mutagenesis. b Receptor residues affecting bias and internalization by mutagenesis. 470 Read et al.

Development and validation of an LC-MS/MS method for detection and quantification of in vivo derived metabolites of [Pyr1]apelin-13 in humans

“…reported in metabolic diseases where it decreased adiposity, serum insulin and increased insulin sensitivity 16,17 ; and in renal diseases where it decreased acute renal injury and fibrosis 18 . It has recently emerged that apelin has pro-tumorigenic effects in various cancer models possibly by promoting angiogenesis and that inhibition of the apelin pathway was protective against tumour growth 14,19 . However, these beneficial effects of apelin peptides are limited by the rapid in vivo metabolism.…”

The Elabela-APJ axis: a promising therapeutic target for heart failure

“…ELA has been demonstrated to have an essential role in heart genesis and proper endoderm differentiation in the zebra fish model via the combination of APJ receptor. The phenotype of ELA mutants in heart development resembles APJ mutants but cannot be duplicated by apelin mutants, implying that ELA is a new-found ligand of APJ [4,14,31]. Soon after, a short, conserved, and secreted peptide named Toddler was discovered during zebra fish embryogenesis with promotion of gastrulation movements [10].…”

“…ELA-54, as a full-length peptide, is detected in the Golgi apparatus, which is cleaved into ELA-32 as its mature secretory form ( Fig. 1) [4,9]. Mature ELA binds to the APJ receptor to become biologically active [4,13,14,17,18].…”

“…1) [4,9]. Mature ELA binds to the APJ receptor to become biologically active [4,13,14,17,18]. Positively charged amino acids in ELA peptides play a critical role in its receptor-binding affinity.…”

“…To address this tough challenge, new clinical therapies for HF need to be developed [3]. Apelin was firstly discovered in 1998 as the endogenous peptide capable of binding the APJ, which was originally described as an orphan G protein-coupled receptor (GPCR) [4,5]. Clinical and experimental studies clearly support multiple cardioprotective effects of the apelin-APJ axis [6][7][8].…”