Cocaine-induced endocannabinoid signaling mediated by sigma-1 receptors and extracellular vesicle secretion

  1. Yoki Nakamura
  2. Dilyan I Dryanovski
  3. Yuriko Kimura
  4. Shelley N Jackson
  5. Amina S Woods
  6. Yuko Yasui
  7. Shang-Yi Tsai
  8. Sachin Patel
  9. Daniel P Covey
  10. Tsung-Ping Su
  11. Carl Lupica  Is a corresponding author
  1. National Institute on Drug Abuse, National Institutes of Health, United States
  2. Vanderbilt University Medical Center, United States
  3. University of Maryland School of Medicine, United States

Abstract

Cocaine is an addictive drug that acts in brain reward areas. Recent evidence suggests that cocaine stimulates synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) in midbrain, increasing dopamine neuron activity via disinhibition. Although a mechanism for cocaine-stimulated 2-AG synthesis is known, our understanding of 2-AG release is limited. In NG108 cells and mouse midbrain tissue we find that 2-AG is localized in non-synaptic extracellular vesicles (EVs) that are secreted in the presence of cocaine via interaction with the chaperone protein sigma-1 receptor (Sig-1R). The release of EVs occurs when cocaine causes dissociation of the Sig-1R from ADP-ribosylation factor (ARF6), a G-protein regulating EV trafficking, leading to activation of myosin light chain kinase (MLCK). Blockade of Sig-1R function, or inhibition of ARF6 or MLCK also prevented cocaine-induced EV release and cocaine-stimulated 2-AG-modulation of inhibitory synapses in DA neurons. Our results implicate the Sig-1R-ARF6 complex in control of EV release and demonstrate that cocaine-mediated 2-AG release can occur via EVs.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Yoki Nakamura

    Cellular Pathobiology Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Dilyan I Dryanovski

    Electrophysiology Research Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yuriko Kimura

    Cellular Pathobiology Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Shelley N Jackson

    Structural Biology Unit, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Amina S Woods

    Structural Biology Unit, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Yuko Yasui

    Cellular Pathobiology Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Shang-Yi Tsai

    Cellular Pathobiology Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Sachin Patel

    Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8052-520X
  9. Daniel P Covey

    Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9596-108X
  10. Tsung-Ping Su

    Cellular Pathobiology Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Carl Lupica

    Electrophysiology Research Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States
    For correspondence
    clupica@mail.nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5375-3263

Funding

National Institute on Drug Abuse (1ZIADA000487-14)

  • Carl Lupica

National Institute on Drug Abuse (1ZIADA000206-33)

  • Tsung-Ping Su

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

Ethics

Animal experimentation: Ethics Statement: All animal procedures were conducted in accordance with the principles as indicated by the NIH Guide for the Care and Use of Laboratory Animals. These animal protocols were also reviewed and approved by the NIDA intramural research program Animal Care and Use Committee, which is fully accredited by the Assessment and Accreditation of Laboratory Animal Care (AAALAC) International (approved protocols: 17-CNRB-15, 16-CNRB-128, 16-INB-1, 16-INB-3, 17-INB-5).

Reviewing Editor

  1. Gary L Westbrook, Oregon Health and Science University, United States

Version history

  1. Received: March 28, 2019
  2. Accepted: October 3, 2019
  3. Accepted Manuscript published: October 9, 2019 (version 1)
  4. Version of Record published: November 12, 2019 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 3,328
    Page views
  • 567
    Downloads
  • 33
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

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)

  1. Yoki Nakamura
  2. Dilyan I Dryanovski
  3. Yuriko Kimura
  4. Shelley N Jackson
  5. Amina S Woods
  6. Yuko Yasui
  7. Shang-Yi Tsai
  8. Sachin Patel
  9. Daniel P Covey
  10. Tsung-Ping Su
  11. Carl Lupica
(2019)
Cocaine-induced endocannabinoid signaling mediated by sigma-1 receptors and extracellular vesicle secretion
eLife 8:e47209.
https://doi.org/10.7554/eLife.47209

Share this article

https://doi.org/10.7554/eLife.47209

Further reading

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Kristian Davidsen, Jonathan S Marvin ... Lucas B Sullivan
    Research Article

    Intracellular levels of the amino acid aspartate are responsive to changes in metabolism in mammalian cells and can correspondingly alter cell function, highlighting the need for robust tools to measure aspartate abundance. However, comprehensive understanding of aspartate metabolism has been limited by the throughput, cost, and static nature of the mass spectrometry (MS)-based measurements that are typically employed to measure aspartate levels. To address these issues, we have developed a green fluorescent protein (GFP)-based sensor of aspartate (jAspSnFR3), where the fluorescence intensity corresponds to aspartate concentration. As a purified protein, the sensor has a 20-fold increase in fluorescence upon aspartate saturation, with dose-dependent fluorescence changes covering a physiologically relevant aspartate concentration range and no significant off target binding. Expressed in mammalian cell lines, sensor intensity correlated with aspartate levels measured by MS and could resolve temporal changes in intracellular aspartate from genetic, pharmacological, and nutritional manipulations. These data demonstrate the utility of jAspSnFR3 and highlight the opportunities it provides for temporally resolved and high-throughput applications of variables that affect aspartate levels.

    1. Cell Biology
    2. Immunology and Inflammation
    Chinky Shiu Chen Liu, Tithi Mandal ... Dipyaman Ganguly
    Research Article

    T cells are crucial for efficient antigen-specific immune responses and thus their migration within the body, to inflamed tissues from circulating blood or to secondary lymphoid organs, plays a very critical role. T cell extravasation in inflamed tissues depends on chemotactic cues and interaction between endothelial adhesion molecules and cellular integrins. A migrating T cell is expected to sense diverse external and membrane-intrinsic mechano-physical cues, but molecular mechanisms of such mechanosensing in cell migration are not established. We explored if the professional mechanosensor Piezo1 plays any role during integrin-dependent chemotaxis of human T cells. We found that deficiency of Piezo1 in human T cells interfered with integrin-dependent cellular motility on ICAM-1-coated surface. Piezo1 recruitment at the leading edge of moving T cells is dependent on and follows focal adhesion formation at the leading edge and local increase in membrane tension upon chemokine receptor activation. Piezo1 recruitment and activation, followed by calcium influx and calpain activation, in turn, are crucial for the integrin LFA1 (CD11a/CD18) recruitment at the leading edge of the chemotactic human T cells. Thus, we find that Piezo1 activation in response to local mechanical cues constitutes a membrane-intrinsic component of the ‘outside-in’ signaling in human T cells, migrating in response to chemokines, that mediates integrin recruitment to the leading edge.