Abstract

The roles of arrestins in regulating G protein coupling and receptor endocytosis following agonist stimulation of G protein-coupled receptors are well characterised. However, their ability to act on their own as direct modulators or activators of signalling remains poorly characterised. Here, arrestin2 intrinsic signalling properties were assessed by forcing the recruitment of this accessory protein to vasopressin V1a or V2 receptors independently of agonist-promoted activation of the receptors. Such induction of a stable interaction with arrestin2 initiated receptor endocytosis leading to intracellular accumulation of the arrestin/receptor complexes. Interestingly, arrestin2 association to a single receptor protomer was sufficient to elicit receptor dimer internalisation. In addition to recapitulating arrestin2 classical actions on receptor trafficking, the receptor activity-independent recruitment of arrestin2 activated the extracellular signal-regulated kinases. In the latter case, recruitment to the receptor itself was not required since kinase activation could be mediated by arrestin2 translocation to the plasma membrane in the absence of any interacting receptor. These data demonstrate that arrestin2 can act as a 'bonafide' signalling molecule even in the absence of activated receptor.