Compartment-specific opioid receptor signaling is selectively modulated by different Dynorphin peptides
- University of Michigan Medical School, United States
- Icahn School of Medicine at Mount Sinai, United States
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
Manojkumar A Puthenveedu
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.
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.
Metrics
-
- 2,006
- views
-
- 290
- downloads
-
- 20
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Compartment-specific opioid receptor signaling is selectively modulated by different Dynorphin peptides
eLife 10:e60270.
https://doi.org/10.7554/eLife.60270
