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

• DOI: 10.3389/fphar.2021.630548
• Publication Date: 2021-03-04T08:50:50Z
• Authors: Yunlu Jiang; Maocai Yan; Chunmei Wang; Qinqin Wang; Xiaoyu Chen; Rumin Zhang; Lei Wan; Bingyuan Ji; Bo Dong; Huiyun Wang; Jing Chen
• Keywords: Pharmacology; 0303 health sciences; 03 medical and health sciences; apelin; arrestin; Elabela; Therapeutics. Pharmacology; RM1-950; apelin receptor; biased signaling

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.