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

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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.

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

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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.

"This ORCID iD identifies the author of this article:" 0000-0002-8151-290X
Wooree Ko

Pharmacology, University of Michigan Medical School, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
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.

"This ORCID iD identifies the author of this article:" 0000-0001-7176-038X
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.

"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.

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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.