Conformational specificity of opioid receptors is determined by subcellular location irrespective of agonist

  1. Stephanie E Crilly
  2. Wooree Ko
  3. Zara Y Weinberg
  4. Manojkumar A Puthenveedu  Is a corresponding author
  1. University of Michigan Medical School, United States
  2. University of California, San Francisco, United States

Abstract

The prevailing model for the variety in drug responses is that they stabilize distinct active states of their G protein-coupled receptor (GPCR) targets, allowing coupling to different effectors. However, whether the same ligand generates different GPCR active states based on the immediate environment of receptors is not known. Here we address this question using spatially resolved imaging of conformational biosensors that read out distinct active conformations of the δ-opioid receptor (DOR), a physiologically relevant GPCR localized to Golgi and the surface in neuronal cells. We show that Golgi and surface pools of DOR both inhibit cAMP, but engage distinct conformational biosensors in response to the same ligand in rat neuroendocrine cells. Further, DOR recruits arrestins on the surface but not the Golgi. Our results suggest that the local environment determines the active states of receptors for any given drug, allowing GPCRs to couple to different effectors at different subcellular locations.

Data availability

All data generated and analyzed have been included in this study. No new sequencing data or structural data are reported.

Article and author information

Author details

  1. Stephanie E Crilly

    Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8151-290X
  2. Wooree Ko

    Pharmacology, University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Zara Y Weinberg

    Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7176-038X
  4. Manojkumar A Puthenveedu

    Pharmacology, University of Michigan Medical School, Ann Arbor, United States
    For correspondence
    puthenve@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3177-4231

Funding

National Science Foundation (1256260)

  • Stephanie E Crilly

National Institute of General Medical Sciences (GM117425)

  • Manojkumar A Puthenveedu

National Science Foundation (1935926)

  • Manojkumar A Puthenveedu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Jonathan A Cooper, Fred Hutchinson Cancer Research Centre, United States

Publication history

  1. Received: February 12, 2021
  2. Accepted: May 19, 2021
  3. Accepted Manuscript published: May 20, 2021 (version 1)
  4. Version of Record published: June 16, 2021 (version 2)

Copyright

© 2021, Crilly et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Stephanie E Crilly
  2. Wooree Ko
  3. Zara Y Weinberg
  4. Manojkumar A Puthenveedu
(2021)
Conformational specificity of opioid receptors is determined by subcellular location irrespective of agonist
eLife 10:e67478.
https://doi.org/10.7554/eLife.67478

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