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J Biol Chem. 2014 Aug 29;289(35):24599-610. doi: 10.1074/jbc.M113.541698. Epub 2014 Jul 10.

Biased signaling favoring gi over β-arrestin promoted by an apelin fragment lacking the C-terminal phenylalanine.

Author information

  • 1From the Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, INSERM U1050, Paris F-75005, France, the Center for Interdisciplinary Research in Biology, Collège de France, Paris F-75005, France, CNRS, UMR 7241, Paris F-75005, France, and.
  • 2the Department of Biochemistry, Institute for Research in Immunology and Cancer, and Groupe de Recherche Universitaire sur le Médicament, Université de Montréal, Montréal, Québec H3T 1J4, Canada.
  • 3From the Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, INSERM U1050, Paris F-75005, France, the Center for Interdisciplinary Research in Biology, Collège de France, Paris F-75005, France, CNRS, UMR 7241, Paris F-75005, France, and c.llorens-cortes@college-de-france.fr.

Abstract

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 as a Gi-independent but β-arrestin-dependent signaling pathway that could involve MAPKs. For this purpose, we have used apelin fragments K17F and K16P (K17F with the C-terminal Phe deleted), 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 providing 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.

KEYWORDS:

Apelin; Apelin Receptor; Arrestin; Cell Signaling; Extracellular Signal-regulated Kinase (ERK); G Protein; G Protein-coupled Receptor (GPCR); Mitogen-activated Protein Kinase (MAPK); Pertussis Toxin

PMID:
25012663
PMCID:
PMC4148883
DOI:
10.1074/jbc.M113.541698
[PubMed - indexed for MEDLINE]
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