STIM1-dependent peripheral coupling governs the contractility of vascular smooth muscle cells

  1. Vivek Krishnan
  2. Sher Ali
  3. Albert L Gonzales
  4. Pratish Thakore
  5. Caoimhin S Griffin
  6. Evan Yamasaki
  7. Michael G Alvarado
  8. Martin T Johnson
  9. Mohamed Trebak
  10. Scott Earley  Is a corresponding author
  1. University of Nevada Reno, United States
  2. University of Nevada, Reno, United States
  3. Penn State University, United States
  4. University of Pittsburgh, United States

Abstract

Peripheral coupling between the sarcoplasmic reticulum (SR) and plasma membrane (PM) forms signaling complexes that regulate the membrane potential and contractility of vascular smooth muscle cells (VSMCs). The mechanisms responsible for these membrane interactions are poorly understood. In many cells, STIM1 (stromal-interaction molecule 1), a single transmembrane-domain protein that resides in the endoplasmic reticulum (ER), transiently moves to ER-PM junctions in response to depletion of ER Ca2+ stores and initiates store-operated Ca2+ entry (SOCE). Fully differentiated VSMCs express STIM1 but exhibit only marginal SOCE activity. We hypothesized that STIM1 is constitutively active in contractile VSMCs and maintains peripheral coupling. In support of this concept, we found that the number and size of SR-PM interacting sites were decreased, and SR-dependent Ca2+ signaling processes were disrupted in freshly isolated cerebral artery SMCs from tamoxifen-inducible, SMC-specific STIM1-knockout (Stim1-smKO) mice. VSMCs from Stim1-smKO mice also exhibited a reduction in nanoscale colocalization between Ca2+-release sites on the SR and Ca2+-activated ion channels on the PM, accompanied by diminished channel activity. Stim1-smKO mice were hypotensive, and resistance arteries isolated from them displayed blunted contractility. These data suggest that STIM1 - independent of SR Ca2+ store depletion - is critically important for stable peripheral coupling in contractile VSMCs.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. All source data files and blots images have been provided.

Article and author information

Author details

  1. Vivek Krishnan

    Department of Pharmacology, University of Nevada Reno, Reno, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5064-4910
  2. Sher Ali

    Department of Pharmacology, University of Nevada Reno, Reno, United States
    Competing interests
    No competing interests declared.
  3. Albert L Gonzales

    Department of Physiology and Cell Biology, University of Nevada Reno, Reno, United States
    Competing interests
    No competing interests declared.
  4. Pratish Thakore

    Department of Pharmacology, University of Nevada, Reno, Reno, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2086-5453
  5. Caoimhin S Griffin

    Department of Pharmacology, University of Nevada Reno, Reno, United States
    Competing interests
    No competing interests declared.
  6. Evan Yamasaki

    Department of Pharmacology, University of Nevada Reno, Reno, United States
    Competing interests
    No competing interests declared.
  7. Michael G Alvarado

    Department of Pharmacology, University of Nevada Reno, Reno, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3489-9021
  8. Martin T Johnson

    Department of Cellular and Molecular Physiology, Penn State University, Hershey, United States
    Competing interests
    No competing interests declared.
  9. Mohamed Trebak

    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    Mohamed Trebak, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6759-864X
  10. Scott Earley

    Department of Pharmacology, University of Nevada Reno, Reno, United States
    For correspondence
    searley@med.unr.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9560-2941

Funding

National Heart, Lung, and Blood Institute (R35HL155008)

  • Scott Earley

National Heart, Lung, and Blood Institute (R35HL150778)

  • Mohamed Trebak

National Heart, Lung, and Blood Institute (K01HL138215)

  • Albert L Gonzales

National Heart, Lung, and Blood Institute (R01HL137852)

  • Scott Earley

National Heart, Lung, and Blood Institute (R01HL091905)

  • Scott Earley

National Heart, Lung, and Blood Institute (R01HL139585)

  • Scott Earley

National Heart, Lung, and Blood Institute (R01HL122770)

  • Scott Earley

National Heart, Lung, and Blood Institute (R01HL146054)

  • Scott Earley

National Institute of Neurological Disorders and Stroke (RF1NS110044)

  • Scott Earley

National Institute of Neurological Disorders and Stroke (R61NS115132)

  • Scott Earley

National Institute of General Medical Sciences (P20GM130459)

  • Scott Earley

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

Reviewing Editor

  1. Murali Prakriya, Northwestern University, United States

Ethics

Animal experimentation: All animal studies were performed in strict accordance with the guidelines of the Institutional Animal Care and Use Committee (IACUC) of the University of Nevada, Reno, and in accordance with the approved protocol 20-06-2020. All surgery was performed under isoflurane anesthesia, and every effort was made to minimize suffering, including preoperative analgesia provided by subcutaneous injection of 50 µg/kg buprenorphine.

Version history

  1. Received: May 12, 2021
  2. Preprint posted: May 26, 2021 (view preprint)
  3. Accepted: February 10, 2022
  4. Accepted Manuscript published: February 11, 2022 (version 1)
  5. Version of Record published: March 24, 2022 (version 2)

Copyright

© 2022, Krishnan 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. Vivek Krishnan
  2. Sher Ali
  3. Albert L Gonzales
  4. Pratish Thakore
  5. Caoimhin S Griffin
  6. Evan Yamasaki
  7. Michael G Alvarado
  8. Martin T Johnson
  9. Mohamed Trebak
  10. Scott Earley
(2022)
STIM1-dependent peripheral coupling governs the contractility of vascular smooth muscle cells
eLife 11:e70278.
https://doi.org/10.7554/eLife.70278

Share this article

https://doi.org/10.7554/eLife.70278

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