1. Neuroscience

a1 adrenergic receptor - PKC - Pyk2 - Src signaling boosts L-type Ca2+ channel Cav1.2 activity and long-term potentiation in rodents

  1. Kwun Nok Mimi Man
  2. Peter Bartels
  3. Peter B Henderson
  4. Karam Kim
  5. Mei Shi
  6. Mingxu Zhang
  7. Sheng-Yang Ho
  8. Madeline Nieves-Cintron
  9. Manuel F Navedo
  10. Mary C Horne  Is a corresponding author
  11. Johannes W Hell  Is a corresponding author
  1. University of California, Davis, United States
  2. University of Iowa, United States
https://doi.org/10.7554/eLife.79648
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Cite this article
  1. Kwun Nok Mimi Man
  2. Peter Bartels
  3. Peter B Henderson
  4. Karam Kim
  5. Mei Shi
  6. Mingxu Zhang
  7. Sheng-Yang Ho
  8. Madeline Nieves-Cintron
  9. Manuel F Navedo
  10. Mary C Horne
  11. Johannes W Hell
(2023)
a1 adrenergic receptor - PKC - Pyk2 - Src signaling boosts L-type Ca2+ channel Cav1.2 activity and long-term potentiation in rodents
eLife 12:e79648.
https://doi.org/10.7554/eLife.79648
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Abstract

The cellular mechanisms mediating norepinephrine functions in brain to result in behaviors are unknown. We identified the L-type Ca2+ channel (LTCC) CaV1.2 as a principal target for Gq-coupled a1-adrenergic receptors (ARs). a1AR signaling increased LTCC activity in hippocampal neurons. This regulation required PKC-mediated activation of the tyrosine kinases Pyk2 and, downstream, Src. Pyk2 and Src were associated with CaV1.2. In model neuroendocrine PC12 cells, stimulation of PKC induced tyrosine phosphorylation of CaV1.2, a modification abrogated by inhibition of Pyk2 and Src. Upregulation of LTCC activity by a1AR and formation of a signaling complex with PKC, Pyk2, and Src suggests that CaV1.2 is a central conduit for signaling by norepinephrine. Indeed, a form of hippocampal LTP in young mice requires both the LTCC and a1AR stimulation. Inhibition of Pyk2 and Src blocked this LTP, indicating that enhancement of CaV1.2 activity via a1AR - Pyk2 - Src signaling regulates synaptic strength.

Data availability

Raw datasets are available on Dryad (https://doi.org/10.25338/B86G9K).

The following data sets were generated

Article and author information

Author details

  1. Kwun Nok Mimi Man

    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:" 0000-0002-0132-9129

  2. Peter Bartels

    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:" 0000-0001-5852-1835

  3. Peter B Henderson

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

  4. Karam Kim

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

  5. Mei Shi

    Department of Pharmacology, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Mingxu Zhang

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

  7. Sheng-Yang Ho

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

  8. Madeline Nieves-Cintron

    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:" 0000-0003-1935-8400

  9. 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

  10. Mary C Horne

    Department of Pharmacology, University of California, Davis, Davis, United States
    For correspondence
    mhorne@ucdavis.edu
    Competing interests
    The authors declare that no competing interests exist.

  11. Johannes W Hell

    Department of Pharmacology, University of California, Davis, Davis, United States
    For correspondence
    jwhell@ucdavis.edu
    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

Funding

National Institutes of Health (R01 MH097887)

  • Johannes W Hell

National Institutes of Health (RF1 AG055357)

  • Johannes W Hell

National Institutes of Health (R01 HL098200)

  • Manuel F Navedo

National Institutes of Health (R01 HL121059)

  • Manuel F Navedo

National Institutes of Health (T32 GM099608)

  • Peter B Henderson

National Institutes of Health (R01 NS123050)

  • Madeline Nieves-Cintron

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 followed NIH guidelines and had been approved by the Institutional Animal Care and Use Committees (IACUC) at UC Davis (Protocol #20673 and #22403).

Reviewing Editor

  1. Yukiko Goda, Okinawa Institute of Science and Technology, Japan

Version history

  1. Received: April 21, 2022
  2. Preprint posted: July 3, 2022 (view preprint)
  3. Accepted: June 19, 2023
  4. Accepted Manuscript published: June 20, 2023 (version 1)
  5. Version of Record published: July 6, 2023 (version 2)

Copyright

© 2023, Man 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. Kwun Nok Mimi Man
  2. Peter Bartels
  3. Peter B Henderson
  4. Karam Kim
  5. Mei Shi
  6. Mingxu Zhang
  7. Sheng-Yang Ho
  8. Madeline Nieves-Cintron
  9. Manuel F Navedo
  10. Mary C Horne
  11. Johannes W Hell
(2023)
a1 adrenergic receptor - PKC - Pyk2 - Src signaling boosts L-type Ca2+ channel Cav1.2 activity and long-term potentiation in rodents
eLife 12:e79648.
https://doi.org/10.7554/eLife.79648

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