1. Cell Biology
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Compartment-specific opioid receptor signaling is selectively modulated by different Dynorphin peptides

  1. Jennifer M Kunselman
  2. Achla Gupta
  3. Ivone gomes
  4. Lakshmi A Devi
  5. Manojkumar A Puthenveedu  Is a corresponding author
  1. University of Michigan Medical School, United States
  2. Icahn School of Medicine at Mount Sinai, United States
Research Article
  • Cited 3
  • Views 1,149
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Cite this article as: eLife 2021;10:e60270 doi: 10.7554/eLife.60270

Abstract

Many signal transduction systems have an apparent redundancy built into them, where multiple physiological agonists activate the same receptors. Whether this is true redundancy, or whether this provides an as-yet unrecognized specificity in downstream signaling, is not well understood. We address this question using the kappa opioid receptor (KOR), a physiologically relevant G protein-coupled receptor (GPCR) that is activated by multiple members of the Dynorphin family of opioid peptides. We show that two related peptides, Dynorphin A and Dynorphin B, bind and activate KOR to similar extents in mammalian neuroendocrine cells and rat striatal neurons, but localize KOR to distinct intracellular compartments and drive different post-endocytic fates of the receptor. Strikingly, localization of KOR to the degradative pathway by Dynorphin A induces sustained KOR signaling from these compartments. Our results suggest that seemingly redundant endogenous peptides can fine-tune signaling by regulating the spatiotemporal profile of KOR signaling.

Data availability

Data generated and analyzed in this study are included in the manuscript. The study did not generate new sequencing or structural data.

Article and author information

Author details

  1. Jennifer M Kunselman

    University of Michigan Medical School, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Achla Gupta

    Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ivone gomes

    Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Lakshmi A Devi

    Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Manojkumar A Puthenveedu

    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 Institute of General Medical Sciences (T32GM007315)

  • Jennifer M Kunselman

National Institute of General Medical Sciences (GM117425)

  • Manojkumar A Puthenveedu

National Science Foundation (1935926)

  • Manojkumar A Puthenveedu

National Institute of Neurological Disorders and Stroke (NS026880)

  • Lakshmi A Devi

National Institute on Drug Abuse (DA008863)

  • Lakshmi A Devi

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

Reviewing Editor

  1. Suzanne R Pfeffer, Stanford University School of Medicine, United States

Publication history

  1. Received: June 23, 2020
  2. Accepted: April 19, 2021
  3. Accepted Manuscript published: April 28, 2021 (version 1)
  4. Version of Record published: May 11, 2021 (version 2)

Copyright

© 2021, Kunselman 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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