Apelin‐13 induces ERK1/2 but not p38 MAPK activation through coupling of the human apelin receptor to the G i2 pathway

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 G i ‐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 G i2 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 G i2 cascade. In conclusion, the ERK1/ 2, but not p38 MAPKpathway is activated by apelin‐13 through coupling of human APJ to G i2‐ protein, which contributes to cellular responses.