Biased signaling favoring Gi over {beta}-arrestin promoted by an apelin fragment lacking the C-terminal phenylalanine. [Cell Biology]

July 10th, 2014 by Ceraudo, E., Galanth, C., Carpentier, E., Banegas-Font, I., Schonegge, A.-M., Alvear-Perez, R., Iturrioz, X., Bouvier, M., Llorens-Cortes, C.

Apelin plays a prominent role in body fluid and cardiovascular homeostasis. We previously showed that the C-terminal Phe of apelin 17 (K17F) is crucial for triggering apelin receptor internalization and decreasing blood pressure (BP) but is not required for apelin binding or Gi-protein coupling. Based on these findings, we hypothesized that the important role of the C-terminal Phe in BP decrease may be Gi-independent but β-arrestin-dependent signaling pathway which could involve MAPKs. For this purpose, we have used apelin fragments K17F and K16P (K17F deleted of its C-terminal Phe), which exhibit opposite profiles on apelin receptor internalization and BP. Using BRET-based biosensors, we showed that whereas K17F activates Gi and promotes β-arrestin recruitment to the receptor, K16P had a much reduced ability to promote β-arrestin recruitment while maintaining its Gi activating property, revealing the biased agonist character of K16P. We further show that both β-arrestin recruitment and apelin receptor internalization contribute to the K17F-stimulated ERK1/2 activity whereas the K16P-promoted ERK1/2 activity is entirely Gi-dependent. In addition to provide new insights on the structural basis underlying the functional selectivity of apelin peptides, our study indicates that the β-arrestin-dependent ERK1/2 activation and not the Gi-dependent signaling, may participate in K17F-induced BP decrease.