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

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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.

Data availability

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

The following previously published data sets were used

1. T Tanabe
2. H Takeshima
3. A Mikami
4. V Flockerzi
5. H Takahashi
6. K Kangawa
7. M Kojima
8. H Matsuo
9. T Hirose
10. S Numa
(1987) DHPR sequence
https://www.nature.com/articles/328313a0.

https://www.nature.com/articles/328313a0

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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.

"This ORCID iD identifies the author of this article:" 0000-0001-8075-8812
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.

"This ORCID iD identifies the author of this article:" 0000-0002-6811-6283
Klaus R Liedl

Theoretical Chemistry, University of Innsbruck, Innsbruck, Austria

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0985-2299
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.

"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.

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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.