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Dual RXR motifs regulate nerve growth factor–mediated intracellular retention of the delta opioid receptor

The delta opioid receptor (DOR), a physiologically relevant prototype for G protein–coupled receptors, is retained in intracellular compartments in neuronal cells. This retention is mediated by a nerve growth factor (NGF)-regulated checkpoint that delays the export of DOR from the trans-Golgi networ...

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Autores principales: Shiwarski, Daniel J., Crilly, Stephanie E., Dates, Andrew, Puthenveedu, Manojkumar A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589700/
https://www.ncbi.nlm.nih.gov/pubmed/30601694
http://dx.doi.org/10.1091/mbc.E18-05-0292
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author Shiwarski, Daniel J.
Crilly, Stephanie E.
Dates, Andrew
Puthenveedu, Manojkumar A.
author_facet Shiwarski, Daniel J.
Crilly, Stephanie E.
Dates, Andrew
Puthenveedu, Manojkumar A.
author_sort Shiwarski, Daniel J.
collection PubMed
description The delta opioid receptor (DOR), a physiologically relevant prototype for G protein–coupled receptors, is retained in intracellular compartments in neuronal cells. This retention is mediated by a nerve growth factor (NGF)-regulated checkpoint that delays the export of DOR from the trans-Golgi network. How DOR is selectively retained in the Golgi, in the midst of dynamic membrane transport and cargo export, is a fundamental unanswered question. Here we address this by investigating sequence elements on DOR that regulate DOR surface delivery, focusing on the C-terminal tail of DOR that is sufficient for NGF-mediated regulation. By systematic mutational analysis, we define conserved dual bi-arginine (RXR) motifs that are required for NGF- and phosphoinositide-regulated DOR export from intracellular compartments in neuroendocrine cells. These motifs were required to bind the coatomer protein I (COPI) complex, a vesicle coat complex that mediates primarily retrograde cargo traffic in the Golgi. Our results suggest that interactions of DOR with COPI, via atypical COPI motifs on the C-terminal tail, retain DOR in the Golgi. These interactions could provide a point of regulation of DOR export and delivery by extracellular signaling pathways.
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spelling pubmed-65897002019-07-10 Dual RXR motifs regulate nerve growth factor–mediated intracellular retention of the delta opioid receptor Shiwarski, Daniel J. Crilly, Stephanie E. Dates, Andrew Puthenveedu, Manojkumar A. Mol Biol Cell Articles The delta opioid receptor (DOR), a physiologically relevant prototype for G protein–coupled receptors, is retained in intracellular compartments in neuronal cells. This retention is mediated by a nerve growth factor (NGF)-regulated checkpoint that delays the export of DOR from the trans-Golgi network. How DOR is selectively retained in the Golgi, in the midst of dynamic membrane transport and cargo export, is a fundamental unanswered question. Here we address this by investigating sequence elements on DOR that regulate DOR surface delivery, focusing on the C-terminal tail of DOR that is sufficient for NGF-mediated regulation. By systematic mutational analysis, we define conserved dual bi-arginine (RXR) motifs that are required for NGF- and phosphoinositide-regulated DOR export from intracellular compartments in neuroendocrine cells. These motifs were required to bind the coatomer protein I (COPI) complex, a vesicle coat complex that mediates primarily retrograde cargo traffic in the Golgi. Our results suggest that interactions of DOR with COPI, via atypical COPI motifs on the C-terminal tail, retain DOR in the Golgi. These interactions could provide a point of regulation of DOR export and delivery by extracellular signaling pathways. The American Society for Cell Biology 2019-03-01 /pmc/articles/PMC6589700/ /pubmed/30601694 http://dx.doi.org/10.1091/mbc.E18-05-0292 Text en © 2019 Shiwarski, Crilly, et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0 This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License.
spellingShingle Articles
Shiwarski, Daniel J.
Crilly, Stephanie E.
Dates, Andrew
Puthenveedu, Manojkumar A.
Dual RXR motifs regulate nerve growth factor–mediated intracellular retention of the delta opioid receptor
title Dual RXR motifs regulate nerve growth factor–mediated intracellular retention of the delta opioid receptor
title_full Dual RXR motifs regulate nerve growth factor–mediated intracellular retention of the delta opioid receptor
title_fullStr Dual RXR motifs regulate nerve growth factor–mediated intracellular retention of the delta opioid receptor
title_full_unstemmed Dual RXR motifs regulate nerve growth factor–mediated intracellular retention of the delta opioid receptor
title_short Dual RXR motifs regulate nerve growth factor–mediated intracellular retention of the delta opioid receptor
title_sort dual rxr motifs regulate nerve growth factor–mediated intracellular retention of the delta opioid receptor
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589700/
https://www.ncbi.nlm.nih.gov/pubmed/30601694
http://dx.doi.org/10.1091/mbc.E18-05-0292
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