1. Neuroscience

Convergent, functionally independent signaling by mu and delta opioid receptors in hippocampal parvalbumin interneurons

  1. Xinyi Jenny He
  2. Janki Patel
  3. Connor E Weiss
  4. Xiang Ma
  5. Brenda L Bloodgood
  6. Matthew Ryan Banghart  Is a corresponding author
  1. University of California San Diego, United States
  2. University of California, San Diego, United States
https://doi.org/10.7554/eLife.69746
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  1. Xinyi Jenny He
  2. Janki Patel
  3. Connor E Weiss
  4. Xiang Ma
  5. Brenda L Bloodgood
  6. Matthew Ryan Banghart
(2021)
Convergent, functionally independent signaling by mu and delta opioid receptors in hippocampal parvalbumin interneurons
eLife 10:e69746.
https://doi.org/10.7554/eLife.69746
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Abstract

neuronal sensitivity to neuromodulators and therapeutic drugs. Mu and Delta opioid receptors (MORs and DORs) can interact when overexpressed in the same cells, but whether co-expression of endogenous MORs and DORs in neurons leads to functional interactions is unclear. Here, in mice, we show that both MORs and DORs inhibit parvalbumin-expressing basket cells (PV-BCs) in hippocampal CA1 through partially occlusive signaling pathways that terminate on somato-dendritic potassium channels and presynaptic calcium channels. Using photoactivatable opioid neuropeptides, we find that DORs dominate the response to enkephalin in terms of both ligand-sensitivity and kinetics, which may be due to relatively low expression levels of MOR. Opioid-activated potassium channels do not show heterologous desensitization, indicating that MORs and DORs signal independently. In a direct test for heteromeric functional interactions, the DOR antagonist TIPP-Psi does not alter the kinetics or potency of either the potassium channel or synaptic responses to photorelease of the MOR agonist DAMGO. Thus, aside from largely redundant and convergent signaling, MORs and DORs do not functionally interact in PV-BCs in a way that impacts somato-dendritic potassium currents or synaptic transmission. These findings imply that crosstalk between MORs and DORs, either in the form of physical interactions or synergistic intracellular signaling, is not a preordained outcome of co-expression in neurons.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures.

Article and author information

Author details

  1. Xinyi Jenny He

    Biological Sciences, University of California San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3884-0596

  2. Janki Patel

    University of California San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Connor E Weiss

    University of California San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Xiang Ma

    University of California San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9164-8608

  5. Brenda L Bloodgood

    University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4797-9119

  6. Matthew Ryan Banghart

    University of California San Diego, San Diego, United States
    For correspondence
    mbanghart@ucsd.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7248-2932

Funding

National Institute on Drug Abuse (R00DA034648)

  • Matthew Ryan Banghart

National Institute of General Medical Sciences (R35GM133802)

  • Matthew Ryan Banghart

National Institute of Neurological Disorders and Stroke (U01NS113295)

  • Matthew Ryan Banghart

National Institute of Mental Health (U01NS113295)

  • Matthew Ryan Banghart

Brain and Behavior Research Foundation (NARSAD Young Investigators Award)

  • Matthew Ryan Banghart

Esther A. and Joseph Klingenstein Fund (Klingenstein-Simons Fellowship in Neuroscience)

  • Matthew Ryan Banghart

National Institute of General Medical Sciences (T32GM007240)

  • Xinyi Jenny He

National Institute of Neurological Disorders and Stroke (R01NS111162)

  • Brenda L Bloodgood

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

Ethics

Animal experimentation: All procedures were performed in accordance with protocols approved by the University of California San Diego Institutional Animal Care and Use Committee (IACUC) following guidelines described in the the US National Institutes of Health Guide for Care and Use of Laboratory Animals (UCSD IACUC protocol S16171). All surgery was performed under isoflurane anesthesia.

Copyright

© 2021, He 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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  1. Xinyi Jenny He
  2. Janki Patel
  3. Connor E Weiss
  4. Xiang Ma
  5. Brenda L Bloodgood
  6. Matthew Ryan Banghart
(2021)
Convergent, functionally independent signaling by mu and delta opioid receptors in hippocampal parvalbumin interneurons
eLife 10:e69746.
https://doi.org/10.7554/eLife.69746

Share this article

https://doi.org/10.7554/eLife.69746

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Further reading

    1. Neuroscience

    Functional independence of endogenous μ- and δ-opioid receptors co-expressed in cholinergic interneurons

    Seksiri Arttamangkul, Emily J Platt ... David Farrens
    Research Article Updated

    Class A G-protein-coupled receptors (GPCRs) normally function as monomers, although evidence from heterologous expression systems suggests that they may sometimes form homodimers and/or heterodimers. This study aims to evaluate possible functional interplay of endogenous µ- and δ-opioid receptors (MORs and DORs) in mouse neurons. Detecting GPCR dimers in native tissues, however, has been challenging. Previously, MORs and DORs co-expressed in transfected cells have been reported to form heterodimers, and their possible co-localization in neurons has been studied in knock-in mice expressing genetically engineered receptors fused to fluorescent proteins. Here, we find that single cholinergic neurons in the mouse striatum endogenously express both MORs and DORs. The receptors on neurons from live brain slices were fluorescently labeled with a ligand-directed labeling reagent, NAI-A594. The selective activation of MORs and DORs, with DAMGO (µ-agonist) and deltorphin (δ-agonist) inhibited spontaneous firing in all cells examined. In the continued presence of agonist, the firing rate returned to baseline as the result of receptor desensitization with the application of deltorphin but was less observed with the application of DAMGO. In addition, agonist-induced internalization of DORs but not MORs was detected. When MORs and DORs were activated simultaneously with [Met5]-enkephalin, desensitization of MORs was facilitated but internalization was not increased. Together, these results indicate that while MORs and DORs are expressed in single striatal cholinergic interneurons, the two receptors function independently.