Local activation of focal adhesion kinase orchestrates the positioning of presynaptic scaffold proteins and Ca2+ signalling to control glucose dependent insulin secretion

  1. Dillon Jevon
  2. Kylie Deng
  3. Nicole Hallahan
  4. Krish Kumar
  5. Jason Tong
  6. Wan Jun Gan
  7. Clara Tran
  8. Marcela M Bilek
  9. Peter Thorn  Is a corresponding author
  1. University of Sydney, Australia
  2. National University of Singapore, Singapore

Abstract

A developing understanding suggests that spatial compartmentalisation in pancreatic β cells is critical in controlling insulin secretion. To investigate the mechanisms, we have developed live-cell sub-cellular imaging methods using the mouse organotypic pancreatic slice. We demonstrate that the organotypic pancreatic slice, when compared with isolated islets, preserves intact β cell structure, and enhances glucose dependent Ca2+ responses and insulin secretion. Using the slice technique, we have discovered the essential role of local activation of integrins and the downstream component, focal adhesion kinase, in regulating β cells. Integrins and focal adhesion kinase are exclusively activated at the β cell capillary interface and using in situ and in vitro models we show their activation both positions presynaptic scaffold proteins, like ELKS and liprin, and regulates glucose dependent Ca2+ responses and insulin secretion. We conclude that focal adhesion kinase orchestrates the final steps of glucose dependent insulin secretion within the restricted domain where β cells contact the islet capillaries.

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. Dillon Jevon

    School of Medical Sciences, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  2. Kylie Deng

    School of Medical Sciences, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9096-2574
  3. Nicole Hallahan

    School of Medical Sciences, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Krish Kumar

    School of Medical Sciences, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Jason Tong

    School of Medical Sciences, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1027-3662
  6. Wan Jun Gan

    Mechanobiology Institute, National University of Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  7. Clara Tran

    School of Physics, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Marcela M Bilek

    School of Physics, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  9. Peter Thorn

    School of Medical Sciences, University of Sydney, Sydney, Australia
    For correspondence
    p.thorn@sydney.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3228-770X

Funding

National Health and Medical Research Council (APP1128273)

  • Peter Thorn

Sydney Medical School (SREI)

  • Marcela M Bilek
  • Peter Thorn

Diabetes Australia Research Trust

  • Peter Thorn

Australian Research Council (FL190100216)

  • Marcela M Bilek

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

Reviewing Editor

  1. Reinhard Jahn, Max Planck Institute for Biophysical Chemistry, Germany

Ethics

Animal experimentation: This study was conducted in strict accordance with local animal ethics procedures as approved by the University of Sydney Ethics Committee (2Project number: 019/1642)

Version history

  1. Received: December 10, 2021
  2. Preprint posted: December 23, 2021 (view preprint)
  3. Accepted: May 12, 2022
  4. Accepted Manuscript published: May 13, 2022 (version 1)
  5. Version of Record published: May 23, 2022 (version 2)

Copyright

© 2022, Jevon 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. Dillon Jevon
  2. Kylie Deng
  3. Nicole Hallahan
  4. Krish Kumar
  5. Jason Tong
  6. Wan Jun Gan
  7. Clara Tran
  8. Marcela M Bilek
  9. Peter Thorn
(2022)
Local activation of focal adhesion kinase orchestrates the positioning of presynaptic scaffold proteins and Ca2+ signalling to control glucose dependent insulin secretion
eLife 11:e76262.
https://doi.org/10.7554/eLife.76262

Share this article

https://doi.org/10.7554/eLife.76262

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