Fig. 1: Overview of apelin receptor ligands that regulate the cardiovascular system in health and disease.
a Aligned amino acid sequences of the endogenous apelin receptor peptides, [Pyr1]apelin-13 (upper) and ELA-11 (lower). Amino acids are provided as single letter codes and coloured according to classification, as indicated in figure. b Schematic showing the signalling cascades following ligand binding and activation of apelin receptor present on the cell surface. Canonical Gi protein signalling mediates physiological effects of the apelin receptor, including increasing cardiac contractility, inducing vasodilatation, and antithrombotic action. Prolonged binding of an agonist can facilitate phosphorylation of the receptor by G protein-coupled receptor kinase (GRK), and subsequent recruitment of β-arrestin protein. This typically desensitises and ‘switches off’ receptor signalling by sterically hindering engagement with G protein complexes and inducing internalisation of the receptor. Created in BioRender. Davenport, A. (2024) https://BioRender.com/f02c819. c Chemical structures of two apelin receptor small molecule agonists, CMF-019 (left) and cmpd644 (right). The structures show differences in chemotypes between the two ligands. d Snake plot of the apelin receptor showing the 380 amino acid sequence generated using GPCRdb (https://gpcrdb.org/)37. Colours indicate the residue locations for missense (V38, blue; T89, red; R168, magenta) or frameshift (G45, T227, both yellow) variants identified in individuals recruited to the 100,000 Genomes Project. Six other missense variants (green) were identified but were not further characterised in vitro, as they did not significantly alter cell surface expression or [125I]-apelin-13 radioligand binding compared to wild-type.
