Encoding the β-Arrestin Trafficking Fate of Ghrelin Receptor GHSR1a: C-Tail-Independent Molecular Determinants in GPCRs.

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Toth, K; Nagi, K; Slosky, LM; Rochelle, L; Ray, C; Kaur, S; Shenoy, SK; Caron, MG; Barak, LS

Published Date

  • August 9, 2019

Published In

  • Acs Pharmacol Transl Sci

Volume / Issue

  • 2 / 4

Start / End Page

  • 230 - 246

PubMed ID

  • 32259059

Pubmed Central ID

  • 32259059

Electronic International Standard Serial Number (EISSN)

  • 2575-9108

Digital Object Identifier (DOI)

  • 10.1021/acsptsci.9b00018

Language

  • eng

Conference Location

  • United States