The Effects of Apelin and Elabela Ligands on Apelin Receptor Distinct Signaling Profiles.

Yunlu Jiang,Huiyun Wang,Bo Dong,Xiaoyu Chen,Maocai Yan,Jing Chen,Rumin Zhang,Qinqin Wang,Bingyuan Ji,Lei Wan,Chunmei Wang

doi:10.3389/fphar.2021.630548

Abstract

Apelin and Elabela are endogenous peptide ligands for Apelin receptor (APJ), a widely expressed G protein-coupled receptor. They constitute a spatiotemporal dual ligand system to control APJ signal transduction and function. We investigated the effects of Apelin-13, pGlu1-apelin-13, Apelin-17, Apelin-36, Elabela-21 and Elabela-32 peptides on APJ signal transduction. Whether different ligands are biased to different APJ mediated signal transduction pathways was studied. We observed the different changes of G protein dependent and β-arrestin dependent signaling pathways after APJ was activated by six peptide ligands. We demonstrated that stimulation with APJ ligands resulted in dose-dependent increases in both G protein dependent [cyclic AMP (cAMP), Ca2+ mobilization, and the early phase extracellular related kinase (ERK) activation] and β-arrestin dependent [GRKs, β-arrestin 1, β-arrestin 2, and β2 subunit of the clathrin adaptor AP2] signaling pathways. However, the ligands exhibited distinct signaling profiles. Elabela-32 showed a >1000-fold bias to the β-statin-dependent signaling pathway. These data provide that Apelin-17 was biased toward β-arrestin dependent signaling. Eabela-21 and pGlu1-Apelin-13 exhibited very distinct activities on the G protein dependent pathway. The activity profiles of these ligands could be valuable for the development of drugs with high selectivity for specific APJ downstream signaling pathways.

Highlights

Apelin receptor is a member of the class A family of G protein-coupled receptor (GPCR), which was first reported by O’Dowd et al (1993)
Murza et al demonstrated that some macrocyclic Apelin ligands are biased toward APJ receptor agonists (Murza et al, 2017) and Elabela that binds to APJ, activates the Gαi1 and β-arrestin2 signaling pathways, and induces receptor internalization to its parent endogenous peptide (Murza et al, 2016)
Because of the lack of suitable Elabela radioactive ligand ([125I]-apelin-13 radioligand was used in this assay), we indirectly compared the binding patterns of Apelin and Elabela fragments

Summary

INTRODUCTION

Apelin receptor ( known as APJ, APLNR, and AGTRL1) is a member of the class A family of G protein-coupled receptor (GPCR), which was first reported by O’Dowd et al (1993). The Role of APJ Ligands in Signal Transduction encodes a precursor protein consisting of 77 amino acid residues (Tatemoto et al, 1998), with a signaling peptide at the N-terminus and a number of paired basic amino acids in the central region. Murza et al demonstrated that some macrocyclic Apelin ligands are biased toward APJ receptor agonists (Murza et al, 2017) and Elabela that binds to APJ, activates the Gαi and β-arrestin signaling pathways, and induces receptor internalization to its parent endogenous peptide (Murza et al, 2016).

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION

DATA AVAILABILITY STATEMENT