AKAP79 enables calcineurin to directly suppress protein kinase A activity

  1. Timothy W Church
  2. Parul Tewatia
  3. Saad Hannan
  4. João Antunes
  5. Olivia Eriksson
  6. Trevor G Smart
  7. Jeanette Hellgren Kotaleski
  8. Matthew G Gold  Is a corresponding author
  1. University College London, United Kingdom
  2. KTH Royal Institute of Technology, Sweden

Abstract

Interplay between the second messengers cAMP and Ca2+ is a hallmark of dynamic cellular processes. A common motif is the opposition of the Ca2+-sensitive phosphatase calcineurin and the major cAMP receptor, protein kinase A (PKA). Calcineurin dephosphorylates sites primed by PKA to bring about changes including synaptic long-term depression (LTD). AKAP79 supports signaling of this type by anchoring PKA and calcineurin in tandem. In this study, we discovered that AKAP79 increases the rate of calcineurin dephosphorylation of type II PKA regulatory subunits by an order of magnitude. Fluorescent PKA activity reporter assays, supported by kinetic modeling, show how AKAP79-enhanced calcineurin activity enables suppression of PKA without altering cAMP levels by increasing PKA catalytic subunit capture rate. Experiments with hippocampal neurons indicate that this mechanism contributes towards LTD. This non-canonical mode of PKA regulation may underlie many other cellular processes.

Data availability

Source data files have been provided for figures 1-6, figure 1-supplement 2, figure 1-supplement 3, figure 3-supplement 1, and figure 3-supplement 2.Original images an uncrossed images for Coomassie-stained gels and immunoblots presented in the manuscript are shown in the zipped folder provided as an additional file.A code repository for this study may be accessed at https://github.com/jdgas/AKAP79_PKA. It contains the R code for the ABC method as well as MATLAB code for reproducing figures. The R code has to be run on a computer cluster. The repository also contains the models with a few example parameter sets, the full parameter sample as described above, and supplementary figures with simulations and experimental data for all 0, 0.2, 1 and 2 M cAMP levels with either WT S98A, or S98E RII𝛼 in the reaction mix.

Article and author information

Author details

  1. Timothy W Church

    Neuroscience, Physiology & Pharmacology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5958-6304
  2. Parul Tewatia

    Science of Life Laboratory, School of Computer Science and Communication, KTH Royal Institute of Technology, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  3. Saad Hannan

    Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4594-0808
  4. João Antunes

    Science of Life Laboratory, School of Computer Science and Communication, KTH Royal Institute of Technology, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9635-5145
  5. Olivia Eriksson

    Science of Life Laboratory, School of Computer Science and Communication, KTH Royal Institute of Technology, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0740-4318
  6. Trevor G Smart

    Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9089-5375
  7. Jeanette Hellgren Kotaleski

    Science of Life Laboratory, School of Computer Science and Communication, KTH Royal Institute of Technology, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0550-0739
  8. Matthew G Gold

    Neuroscience, Physiology & Pharmacology, University College London, London, United Kingdom
    For correspondence
    m.gold@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1281-0815

Funding

Wellcome Trust and Royal Society (104194/Z/14/A)

  • Matthew G Gold

BBSRC (BB/N015274/1)

  • Matthew G Gold

Swedish Research Council (VR-M-2017-02806)

  • Matthew G Gold

European Union/Horizon 2020 (945539 Human Brain Project SGA3)

  • Matthew G Gold

Erasmus Scholarship

  • João Antunes

Wellcome Trust (217199/Z/19/Z)

  • Saad Hannan
  • Trevor G Smart

Swedish Research Council (VR-M-2020-01652)

  • Matthew G Gold

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

Reviewing Editor

  1. Amy Andreotti, Iowa State University, United States

Ethics

Animal experimentation: Experiments involving rats were done in accordance with the United Kingdom Animals Act, 1986 and within University College London Animal Research guidelines overseen by the UCL Animal Welfare and Ethical Review Body under project code 14058.

Version history

  1. Received: March 7, 2021
  2. Preprint posted: March 15, 2021 (view preprint)
  3. Accepted: October 4, 2021
  4. Accepted Manuscript published: October 6, 2021 (version 1)
  5. Version of Record published: November 1, 2021 (version 2)

Copyright

© 2021, Church 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. Timothy W Church
  2. Parul Tewatia
  3. Saad Hannan
  4. João Antunes
  5. Olivia Eriksson
  6. Trevor G Smart
  7. Jeanette Hellgren Kotaleski
  8. Matthew G Gold
(2021)
AKAP79 enables calcineurin to directly suppress protein kinase A activity
eLife 10:e68164.
https://doi.org/10.7554/eLife.68164

Share this article

https://doi.org/10.7554/eLife.68164

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