Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form

Agonist-directed interactions with specific beta-arrestins determine mu-opioid receptor trafficking, ubiquitination, and dephosphorylation

Academic Article
uri icon
  • Overview
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

authors

  • Groer, C. E.
  • Schmid, C. L.
  • Jaeger, A. M.
  • Bohn, Laura

publication date

  • 2011

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Morphine and other opiates mediate their effects through activation of the ?-opioid receptor (MOR), and regulation of the MOR has been shown to critically affect receptor responsiveness. Activation of the MOR results in receptor phosphorylation, ?-arrestin recruitment, and internalization. This classical regulatory process can differ, depending on the ligand occupying the receptor. There are two forms of ?-arrestin, ?-arrestin1 and ?-arrestin2 (also known as arrestin2 and arrestin3, respectively); however, most studies have focused on the consequences of recruiting ?-arrestin2 specifically. In this study, we examine the different contributions of ?-arrestin1- and ?-arrestin2-mediated regulation of the MOR by comparing MOR agonists in cells that lack expression of individual or both ?-arrestins. Here we show that morphine only recruits ?-arrestin2, whereas the MOR-selective enkephalin [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]enkephalin (DAMGO), recruits either ?-arrestin. We show that ?-arrestins are required for receptor internalization and that only ?-arrestin2 can rescue morphine-induced MOR internalization, whereas either ?-arrestin can rescue DAMGO-induced MOR internalization. DAMGO activation of the receptor promotes MOR ubiquitination over time. Interestingly, ?-arrestin1 proves to be critical for MOR ubiquitination as modification does not occur in the absence of ?-arrestin1 nor when morphine occupies the receptor. Moreover, the selective interactions between the MOR and ?-arrestin1 facilitate receptor dephosphorylation, which may play a role in the resensitization of the MOR and thereby contribute to overall development of opioid tolerance.
  • Morphine and other opiates mediate their effects through activation of the μ-opioid receptor (MOR), and regulation of the MOR has been shown to critically affect receptor responsiveness. Activation of the MOR results in receptor phosphorylation, β-arrestin recruitment, and internalization. This classical regulatory process can differ, depending on the ligand occupying the receptor. There are two forms of β-arrestin, β-arrestin1 and β-arrestin2 (also known as arrestin2 and arrestin3, respectively); however, most studies have focused on the consequences of recruiting β-arrestin2 specifically. In this study, we examine the different contributions of β-arrestin1- and β-arrestin2-mediated regulation of the MOR by comparing MOR agonists in cells that lack expression of individual or both β-arrestins. Here we show that morphine only recruits β-arrestin2, whereas the MOR-selective enkephalin [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]enkephalin (DAMGO), recruits either β-arrestin. We show that β-arrestins are required for receptor internalization and that only β-arrestin2 can rescue morphine-induced MOR internalization, whereas either β-arrestin can rescue DAMGO-induced MOR internalization. DAMGO activation of the receptor promotes MOR ubiquitination over time. Interestingly, β-arrestin1 proves to be critical for MOR ubiquitination as modification does not occur in the absence of β-arrestin1 nor when morphine occupies the receptor. Moreover, the selective interactions between the MOR and β-arrestin1 facilitate receptor dephosphorylation, which may play a role in the resensitization of the MOR and thereby contribute to overall development of opioid tolerance.

subject areas

  • Analgesics, Opioid
  • Animals
  • Arrestins
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Enkephalins
  • Mice
  • Phosphorylation
  • Protein Transport
  • Receptors, Opioid, mu
  • Ubiquitination
scroll to property group menus

Identity

PubMed Central ID

  • PMC3173119

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M111.248310

PubMed ID

  • 21757712
scroll to property group menus

Additional Document Info

start page

  • 31731

end page

  • 31741

volume

  • 286

issue

  • 36

©2019 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support