1. Cell Biology
  2. Computational and Systems Biology

Highly Localized intracellular Ca2+ signals promote optimal salivary gland fluid secretion

  1. Takahiro Takano
  2. Amanda Wahl
  3. Kai-Ting Huang
  4. Takanori Narita
  5. John Rugis
  6. James Sneyd
  7. David I Yule  Is a corresponding author
  1. University of Rochester School of Medicine and Dentistry, United States
  2. U. Rochester, United States
  3. Nihon University, Japan
  4. University of Auckland, New Zealand
https://doi.org/10.7554/eLife.66170
Share this article
Cite this article
  1. Takahiro Takano
  2. Amanda Wahl
  3. Kai-Ting Huang
  4. Takanori Narita
  5. John Rugis
  6. James Sneyd
  7. David I Yule
(2021)
Highly Localized intracellular Ca2+ signals promote optimal salivary gland fluid secretion
eLife 10:e66170.
https://doi.org/10.7554/eLife.66170
  2. Download BibTeX
  3. Download .RIS

Abstract

Salivary fluid secretion involves an intricate choreography of membrane transporters to result in the trans-epithelial movement of NaCl and water into the acinus lumen. Current models are largely based on experimental observations in enzymatically isolated cells where the Ca2+ signal invariably propagates globally and thus appears ideally suited to activate spatially separated Cl and K channels, present on the apical and basolateral plasma membrane, respectively. We monitored Ca2+ signals and salivary secretion in live mice expressing GCamp6F, following stimulation of the nerves innervating the submandibular gland. Consistent with in vitro studies, Ca2+ signals were initiated in the apical endoplasmic reticulum. In marked contrast to in vitro data, highly localized trains of Ca2+ transients that failed to fully propagate from the apical region were observed. Following stimuli optimum for secretion, large apical-basal gradients were elicited. A new mathematical model, incorporating these data was constructed to probe how salivary secretion can be optimally stimulated by apical Ca2+ signals.

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 2,3,4,5,6,9,10,11

Article and author information

Author details

  1. Takahiro Takano

    Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Amanda Wahl

    Pharmacology and Physiology, U. Rochester, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Kai-Ting Huang

    Pharmacology and Physiology, U. Rochester, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Takanori Narita

    Nihon University, Fujisawa, Japan
    Competing interests
    The authors declare that no competing interests exist.

  5. John Rugis

    Mathematics, University of Auckland, Auckland, New Zealand
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8009-4152

  6. James Sneyd

    Mathematics, University of Auckland, Auckland, New Zealand
    Competing interests
    The authors declare that no competing interests exist.

  7. David I Yule

    Pharmacology and Physiology, U. Rochester, Rochester, United States
    For correspondence
    david_yule@urmc.rochester.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6743-0668

Funding

National Institute of Dental and Craniofacial Research (DE019245)

  • David I Yule

National Institute of Dental and Craniofacial Research (DE014756)

  • David I Yule

Marsden Fund

  • James Sneyd

National Institute of Dental and Craniofacial Research (F31 DE030670)

  • Amanda Wahl

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 animal procedures were approved by University Committee on Animal Resources (UCAR-2001-214E)

Copyright

© 2021, Takano 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.

Metrics

  • 1,825
    views
  • 262
    downloads
  • 26
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Takahiro Takano
  2. Amanda Wahl
  3. Kai-Ting Huang
  4. Takanori Narita
  5. John Rugis
  6. James Sneyd
  7. David I Yule
(2021)
Highly Localized intracellular Ca2+ signals promote optimal salivary gland fluid secretion
eLife 10:e66170.
https://doi.org/10.7554/eLife.66170

Share this article

https://doi.org/10.7554/eLife.66170

Categories and tags

Research organism

Further reading

    1. Cell Biology

    Dysregulated Ca2+ signaling, fluid secretion, and mitochondrial function in a mouse model of early Sjögren’s disease

    Kai-Ting Huang, Larry E Wagner ... David I Yule
    Research Advance

    The molecular mechanisms leading to saliva secretion are largely established, but factors that underlie secretory hypofunction, specifically related to the autoimmune disease Sjögren’s syndrome (SS) are not fully understood. A major conundrum is the lack of association between the severity of salivary gland immune cell infiltration and glandular hypofunction. SS-like disease was induced by treatment with DMXAA, a small molecule agonist of murine STING. We have previously shown that the extent of salivary secretion is correlated with the magnitude of intracellular Ca2+ signals (Takano et al., 2021). Contrary to our expectations, despite a significant reduction in fluid secretion, neural stimulation resulted in enhanced Ca2+ signals with altered spatiotemporal characteristics in vivo. Muscarinic stimulation resulted in reduced activation of the Ca2+-activated Cl- channel, TMEM16a, although there were no changes in channel abundance or absolute sensitivity to Ca2+. Super-resolution microscopy revealed a disruption in the colocalization of Inositol 1,4,5-trisphosphate receptor Ca2+ release channels with TMEM16a, and channel activation was reduced when intracellular Ca2+ buffering was increased. These data indicate altered local peripheral coupling between the channels. Appropriate Ca2+ signaling is also pivotal for mitochondrial morphology and bioenergetics. Disrupted mitochondrial morphology and reduced oxygen consumption rate were observed in DMXAA-treated animals. In summary, early in SS disease, dysregulated Ca2+ signals lead to decreased fluid secretion and disrupted mitochondrial function contributing to salivary gland hypofunction.