title: Apelin-13 induces ERK1/2 but not p38 MAPK activation through coupling of the human apelin receptor to the Gi2 pathway.
abstract: Apelin signaling to the family of mitogen-activated protein kinases (MAPKs), such as extracellular-regulated kinases 1/2 (ERK1/2) and p38 MAPK, through the coupling of apelin receptor (APJ) to G-protein, mediates important pathophysiological responses. Although apelin fragments have been reported to induce ERK1/2 activation through Gi-protein, the intracellular pathways by which APJ activates these MAPKs are only partially understood. Here, using stably transfected human embryonic kidney 293 (HEK293) cells overexpressing human APJ (HEK293-apelinR), we showed that apelin-13 signaling leads to ERK1/2 and p38 MAPK pathways through APJ activation. It was found in HEK293-apelinR cells that ERK1/2 activation was initiated by apelin-13 at 5 min, with the peak of activation occurring at 15 min, and a return to the basal level within 60 min. The activation of ERK1/2 appeared to be dose-dependent with a significant activation being observed at 10 nM apelin-13 and maximal activation at 100 nM. However, phosphorylated-p38 MAPK was not detected in HEK293-apelinR cells treated with apelin-13. We also shown that the apelin-13-induced ERK1/2 activation requires a coupling with pertussis toxin-sensitive G-protein, and that overexpression of dominant-negative Gi2 completely inhibits the apelin-13-induced ERK1/2 activation. In addition, treatment with apelin-13 resulted in a concentration-dependent reduction of forskolin-stimulated cAMP production. It is therefore suggested that apelin-13 activates ERK1/2 but not p38 MAPK, which involves the coupling of APJ to the Gi2 cascade. In conclusion, the ERK1/2, but not p38 MAPK pathway is activated by apelin-13 through coupling of human APJ to Gi2-protein, which contributes to cellular responses.
authors.affiliation: Department of Neurobiology, Taishan Medical College, Taian 271016, China. bbai@tsmc.edu.cn
authors.forename: Bo
authors.initials: B
authors.lastname: Bai
authors.forename: Jiyou
authors.initials: J
authors.lastname: Tang
authors.forename: Haiqing
authors.initials: H
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Yalin
authors.initials: Y
authors.lastname: Li
authors.forename: Wengang
authors.initials: W
authors.lastname: Song
mesh_terms: D000075244:Apelin Receptors; D002460:Cell Line; D004789:Enzyme Activation; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D048053:Mitogen-Activated Protein Kinase 6 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C104575:APLNR protein, human; D000075244:Apelin Receptors; D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled; C495199:apelin-13 peptide; D048052:Mitogen-Activated Protein Kinase 3; D048053:Mitogen-Activated Protein Kinase 6; D048051:p38 Mitogen-Activated Protein Kinases; D051960:GTP-Binding Protein alpha Subunit, Gi2