Encoding the β-Arrestin Trafficking Fate of Ghrelin Receptor GHSR1a: C-Tail-Independent Molecular Determinants in GPCRs
Author | Toth, Krisztian |
Author | Nagi, Karim |
Author | Slosky, Lauren M. |
Author | Rochelle, Lauren |
Author | Ray, Caroline |
Author | Kaur, Suneet |
Author | Shenoy, Sudha K. |
Author | Caron, Marc G. |
Author | Barak, Larry S. |
Available date | 2023-08-28T09:09:50Z |
Publication Date | 2019 |
Publication Name | ACS Pharmacology and Translational Science |
Resource | Scopus |
ISSN | 25759108 |
Abstract | G-protein-coupled receptors (GPCRs) can bias signaling through distinct biochemical pathways that originate from G-protein/receptor and β-arrestin/receptor complexes. Receptor conformations supporting β-arrestin engagement depend on multiple receptor determinants. Using ghrelin receptor GHR1a, we demonstrate by bioluminescence resonance energy transfer and fluorescence microscopy a critical role for its second intracellular loop 2 (ICL2) domain in stabilizing β-arrestin/GHSR1a core interactions and determining receptor trafficking fate. We validate our findings in ICL2 gain- and loss-of-function experiments assessing β-arrestin and ubiquitin-dependent internalization of the CC chemokine receptor, CCR1. Like all CC and CXC subfamily chemokine receptors, CCR1 lacks a critical proline residue found in the ICL2 consensus domain of rhodopsin-family GPCRs. Our study indicates that ICL2, C-tail determinants, and the orthosteric binding pocket that regulates β-arrestin/receptor complex stability are sufficient to encode a broad repertoire of the trafficking fates observed for rhodopsin-family GPCRs, suggesting they provide the essential elements for regulating a large fraction of β-arrestin signaling bias. |
Language | en |
Publisher | American Chemical Society |
Subject | arrestin beta-arrestin bias Boolean BRET CCR1 chemokine endocytosis ghrelin GHSR1a GPCR HIV network receptor trafficking ubiquitin β-arrestin |
Type | Article |
Pagination | 230-246 |
Issue Number | 4 |
Volume Number | 2 |
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