1. Structural Biology and Molecular Biophysics

Pore mutation N617D in the skeletal muscle DHPR blocks Ca2+ influx due to atypical high-affinity Ca2+ binding

  1. Anamika Dayal  Is a corresponding author
  2. Monica L Fernández-Quintero
  3. Klaus R Liedl
  4. Manfred Grabner  Is a corresponding author
  1. Medical University of Innsbruck, Austria
  2. University of Innsbruck, Austria
https://doi.org/10.7554/eLife.63435
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  1. Anamika Dayal
  2. Monica L Fernández-Quintero
  3. Klaus R Liedl
  4. Manfred Grabner
(2021)
Pore mutation N617D in the skeletal muscle DHPR blocks Ca2+ influx due to atypical high-affinity Ca2+ binding
eLife 10:e63435.
https://doi.org/10.7554/eLife.63435
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Abstract

Skeletal muscle excitation-contraction (EC) coupling roots in Ca2+-influx-independent inter-channel signaling between the sarcolemmal dihydropyridine receptor (DHPR) and the ryanodine receptor (RyR1) in the sarcoplasmic reticulum. Although DHPR Ca2+ influx is irrelevant for EC coupling, its putative role in other muscle-physiological and developmental pathways was recently examined using two distinct genetically engineered mouse models carrying Ca2+ non-conducting DHPRs: DHPR(N617D) (Dayal et al., 2017) and DHPR(E1014K) (Lee et al., 2015). Surprisingly, despite complete block of DHPR Ca2+-conductance, histological, biochemical, and physiological results obtained from these two models were contradictory. Here we characterize the permeability and selectivity properties and henceforth the mechanism of Ca2+ non-conductance of DHPR(N617). Our results reveal that only mutant DHPR(N617D) with atypical high-affinity Ca2+ pore-binding is tight for physiologically relevant monovalent cations like Na+ and K+. Consequently, we propose a molecular model of cooperativity between two ion selectivity rings formed by negatively charged residues in the DHPR pore region.

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All data generated or analyzed during this study are included in the manuscript and supporting files.

The following previously published data sets were used

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Author details

  1. Anamika Dayal

    Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
    For correspondence
    anamika.dayal@i-med.ac.at
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8075-8812

  2. Monica L Fernández-Quintero

    Department of Physiology and Medical Physics, University of Innsbruck, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6811-6283

  3. Klaus R Liedl

    Theoretical Chemistry, University of Innsbruck, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0985-2299

  4. Manfred Grabner

    Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
    For correspondence
    manfred.grabner@i-med.ac.at
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5196-4024

Funding

Austrian Science Fund (P23229-B09)

  • Manfred Grabner

Austrian Science Fund (P27392-B21)

  • Anamika Dayal
  • Manfred Grabner

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

Reviewing Editor

  1. Henry M Colecraft, Columbia University, United States

Publication history

  1. Received: September 24, 2020
  2. Accepted: May 28, 2021
  3. Accepted Manuscript published: June 1, 2021 (version 1)
  4. Version of Record published: June 7, 2021 (version 2)
  5. Version of Record updated: June 11, 2021 (version 3)

Copyright

© 2021, Dayal 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. Anamika Dayal
  2. Monica L Fernández-Quintero
  3. Klaus R Liedl
  4. Manfred Grabner
(2021)
Pore mutation N617D in the skeletal muscle DHPR blocks Ca2+ influx due to atypical high-affinity Ca2+ binding
eLife 10:e63435.
https://doi.org/10.7554/eLife.63435

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