1. Cell Biology
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β-blockers augment L-type Ca2+ channel activity by targeting spatially restricted β2AR signaling in neurons

  1. Ao Shen
  2. Dana Chen
  3. Mampreet Kaur
  4. Peter Bartels
  5. Bing Xu
  6. Qian Shi
  7. Joseph M Martinez
  8. Kwun-nok Mimi Man
  9. Madeline Nieves-Cintron
  10. Johannes W Hell
  11. Manuel F Navedo
  12. Xiyong Yu
  13. Yang K Xiang  Is a corresponding author
  1. Guangzhou Medical University, China
  2. University of California, Davis, United States
Research Article
  • Cited 4
  • Views 1,258
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Cite this article as: eLife 2019;8:e49464 doi: 10.7554/eLife.49464

Abstract

G protein-coupled receptors (GPCRs) transduce pleiotropic intracellular signals in mammalian cells. Here, we report neuronal excitability of β-blockers carvedilol and alprenolol at clinically relevant nanomolar concentrations. Carvedilol and alprenolol activate β2AR, which promote G protein signaling and cAMP/PKA activities without action of G protein receptor kinases (GRKs). The cAMP/PKA activities are restricted within the immediate vicinity of activated β2AR, leading to selectively enhance PKA-dependent phosphorylation and stimulation of endogenous L-type calcium channel (LTCC) but not AMPA receptor in rat hippocampal neurons. Moreover, we have engineered a mutant β2AR that lacks the catecholamine binding pocket. This mutant is preferentially activated by carvedilol but not the orthosteric agonist isoproterenol. Carvedilol activates the mutant β2AR in mouse hippocampal neurons augmenting LTCC activity through cAMP/PKA signaling. Together, our study identifies a mechanism by which β-blocker-dependent activation of GPCRs promotes spatially restricted cAMP/PKA signaling to selectively target membrane downstream effectors such as LTCC 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 Figures 1, 2, 3, 4, and 5.

Article and author information

Author details

  1. Ao Shen

    Guangzhou Medical University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Dana Chen

    Department of Pharmacology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Mampreet Kaur

    Department of Pharmacology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Peter Bartels

    Department of Pharmacology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Bing Xu

    Department of Pharmacology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Qian Shi

    Department of Pharmacology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Joseph M Martinez

    Department of Pharmacology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Kwun-nok Mimi Man

    Department of Pharmacology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Madeline Nieves-Cintron

    Department of Pharmacology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Johannes W Hell

    Department of Pharmacology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7960-7531
  11. Manuel F Navedo

    Department of Pharmacology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6864-6594
  12. Xiyong Yu

    Guangzhou Medical University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Yang K Xiang

    Department of Pharmacology, University of California, Davis, Davis, United States
    For correspondence
    ykxiang@ucdavis.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1786-9143

Funding

National Institutes of Health (129376)

  • Yang K Xiang

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#20234) of the University of California at Davis. Every effort was made to minimize suffering.

Reviewing Editor

  1. Mark T Nelson, University of Vermont, United States

Publication history

  1. Received: June 18, 2019
  2. Accepted: October 13, 2019
  3. Accepted Manuscript published: October 14, 2019 (version 1)
  4. Version of Record published: October 24, 2019 (version 2)
  5. Version of Record updated: December 2, 2019 (version 3)

Copyright

© 2019, Shen 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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