1. Neuroscience
  2. Structural Biology and Molecular Biophysics
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Kv2.1 mediates spatial and functional coupling of L-type calcium channels and ryanodine receptors in mammalian neurons

  1. Nicholas C Vierra
  2. Michael Kirmiz
  3. Deborah van der List
  4. L Fernando Santana
  5. James S Trimmer  Is a corresponding author
  1. University of California, Davis, United States
Research Article
  • Cited 4
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Cite this article as: eLife 2019;8:e49953 doi: 10.7554/eLife.49953

Abstract

The voltage-gated K+ channel Kv2.1 serves a major structural role in the soma and proximal dendrites of mammalian brain neurons, tethering the plasma membrane (PM) to endoplasmic reticulum (ER). Although Kv2.1 clustering at neuronal ER-PM junctions (EPJs) is tightly regulated and highly conserved, its function remains unclear. By identifying and evaluating proteins in close spatial proximity to Kv2.1-containing EPJs, we discovered that a significant role of Kv2.1 at EPJs is to promote the clustering and functional coupling of PM L-type Ca2+ channels (LTCCs) to ryanodine receptor (RyR) ER Ca2+ release channels. Kv2.1 clustering also unexpectedly enhanced LTCC opening at polarized membrane potentials. This enabled Kv2.1-LTCC-RyR triads to generate localized Ca2+ release events (i.e., Ca2+ sparks) independently of action potentials. Together, these findings uncover a novel mode of LTCC regulation and establish a unique mechanism whereby Kv2.1-associated EPJs provide a molecular platform for localized somatodendritic Ca2+ signals in mammalian brain neurons.

Article and author information

Author details

  1. Nicholas C Vierra

    Department of Physiology and Membrane Biology, 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:" 0000-0001-7269-5399
  2. Michael Kirmiz

    Department of Neurobiology, Physiology and Behavior, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Deborah van der List

    Department of Physiology and Membrane Biology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. L Fernando Santana

    Department of Physiology and Membrane Biology, 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:" 0000-0002-4297-8029
  5. James S Trimmer

    Department of Physiology and Membrane Biology, University of California, Davis, Davis, United States
    For correspondence
    jtrimmer@ucdavis.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6117-3912

Funding

National Institute of Neurological Disorders and Stroke (R21 NS101648)

  • James S Trimmer

National Heart, Lung, and Blood Institute (R01 HL144071)

  • L Fernando Santana
  • James S Trimmer

National Institute of General Medical Sciences (T32 GM007377)

  • Michael Kirmiz

National Institute of Neurological Disorders and Stroke (F32 NS108519)

  • Nicholas C Vierra

National Institute of Neurological Disorders and Stroke (U01 NS099714)

  • James S Trimmer

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#20485 and #21265) of the University of California, Davis. All perfusions were performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Kenton J Swartz, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States

Publication history

  1. Received: July 5, 2019
  2. Accepted: October 29, 2019
  3. Accepted Manuscript published: October 30, 2019 (version 1)
  4. Version of Record published: November 8, 2019 (version 2)

Copyright

© 2019, Vierra 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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