Divergent ?-arrestin-dependent signaling events are dependent upon sequences within G-protein-coupled receptor C termini.

ABSTRACT: ?-Arrestins are multifunctional adaptor proteins that, upon recruitment to an activated G-protein-coupled receptor, can promote desensitization of G-protein signaling and receptor internalization while simultaneously eliciting an independent signal. The result of ?-arrestin signaling depends upon the activating receptor. For example, activation of two G?(q)-coupled receptors, protease-activated receptor-2 (PAR(2)) and neurokinin-1 receptor (NK1R), results in drastically different signaling events. PAR(2) promotes ?-arrestin-dependent membrane-sequestered extracellular signal-regulated kinase (ERK1/2) activation, cofilin activation, and cell migration, whereas NK1R promotes nuclear ERK1/2 activation and proliferation. Using bioluminescence resonance energy transfer to monitor receptor/?-arrestin interactions in real time, we observe that PAR(2) has a higher apparent affinity for both ?-arrestins than does NK1R, recruits them at a faster rate, and exhibits more rapid desensitization of the G-protein signal. Furthermore, recruitment of ?-arrestins to PAR(2) does not require prior G?(q) signaling events, whereas inhibition of G?(q) signaling intermediates inhibits recruitment of ?-arrestins to NK1R. Using chimeric receptors in which the C terminus of PAR(2) is fused to the N terminus of NK1R and vice versa and a critical Ser/Thr mutant of PAR(2), we demonstrate that interactions between ?-arrestins and specific phosphoresidues in the C termini of each receptor are crucial for determining the rate and magnitude of ?-arrestin recruitment as well as the ultimate signaling outcome.

SUBMITTER: Pal K 

PROVIDER: S-EPMC3561547 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature