Multisite phosphorylation is required for sustained interaction with GRKs and arrestins during rapid {mu}-opioid receptor desensitization

We report how specific multisite phosphorylation controlled the dynamics of GRK and β-arrestin interactions with MOR and show how such phosphorylation mediated receptor desensitization. We showed that GRK2/3 was recruited more quickly than was β-arrestin to a DAMGO-activated MOR. β-Arrestin recruitment required GRK2 activity and MOR phosphorylation, but GRK recruitment also depended on the phosphorylation sites in the C-terminal tail, specifically four serine and threonine residues within the 370TREHPSTANT379 motif. Our results also suggested that other residues outside this motif participated in the initial and transient recruitment of GRK and β-arrestins. We identified two components of high-efficacy agonist desensitization of MOR: a sustained component, which required GRK2-mediated phosphorylation and a potential soluble factor, and a rapid component, which was likely mediated by GRK2 but independent of receptor phosphorylation. Elucidating these complex receptor-effector interactions represents an important step toward a mechanistic understanding of MOR desensitization that leads to the development of tolerance and dependence.

Source: Signal Transduction Knowledge Environment - July 17, 2018 Category: Science Authors: Miess, E., Gondin, A. B., Yousuf, A., Steinborn, R., Mösslein, N., Yang, Y., Göldner, M., Ruland, J. G., Bünemann, M., Krasel, C., Christie, M. J., Halls, M. L., Schulz, S., Canals, M. Tags: STKE Research Articles Source Type: news