Lopez, Ruben; Janicek, Radoslav; Fernandez-Tenorio, Miguel; Courtehoux, Marianne; Matas, Lluis; Gerbaud, Pascale; Gomez, Ana M; Egger, Marcel; Niggli, Ernst (2022). Uptake-leak balance of SR Ca2+ determines arrhythmogenic potential of RyR2R420Q+/- cardiomyocytes. Journal of molecular and cellular cardiology, 170, pp. 1-14. Elsevier 10.1016/j.yjmcc.2022.05.011
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Mutations of the RyR2 are channelopathies that can predispose to life threatening catecholaminergic polymorphic ventricular tachycardias (CPVTs) during exercise or stress. However, the cellular and molecular mechanisms that are causal for the arrhythmias downstream of the β-adrenergic receptor (β-AR) activation are not defined. They may be specific and different for each particular RyR2 mutation. Obvious possibilities are the phosphorylation of the mutated RyR2s or the stimulation of the SR Ca2+ pump (SERCA), which could increase SR Ca2+ loading. Potentially arrhythmogenic Ca2+ signals, such as Ca2+ waves, were recorded and analyzed from WT and RyR2R420Q+/- mouse cardiomyocytes with confocal microscopy after field stimulation at 1 Hz. In RyR2R420Q+/- cardiomyocytes we found a higher occurrence and frequency of Ca2+ waves, particularly upon β-AR stimulation with isoproterenol. This was accompanied by a shorter latency to the first spontaneous wave. Wave velocity from raw traces, as well as amplitude and decay time constant (τ) analyzed in de-skewed traces were comparable in both cell types. To obtain further insight into the role of the SERCA we selectively stimulated SERCA in permeabilized myocytes using Fab fragments of a PLB antibody (2D12). Surprisingly, SERCA stimulation alone resulted in considerably higher wave frequencies than when mimicking β-AR stimulation with cAMP, particularly in RyR2R420Q+/- cardiomyocytes. This may be a consequence of some protective SR Ca2+ unloading resulting from the SR Ca2+ leak via phosphorylated RyR2s in cAMP. Spark-to-spark recovery analysis suggested a remarkably higher Ca2+ release sensitivity in RyR2R420Q+/- cells, both in control and upon β-AR stimulation. Together these findings suggest that the fine balance between SR Ca2+ loading via SERCA and the Ca2+ leak via mutated and phosphorylated RyR2s is an important determinant for the overall cellular arrhythmogenicity prevailing in the RyR2R420Q+/- myocytes.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Physiology |
UniBE Contributor: |
Lopez Dicuru, Ruben Jose, Janicek, Radoslav, Fernandez Tenorio, Miguel, Courtehoux, Marianne, Matas Serrato, Lluis Albert, Egger, Marcel, Niggli, Ernst |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
0022-2828 |
Publisher: |
Elsevier |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
02 Jun 2022 16:08 |
Last Modified: |
05 Dec 2022 16:20 |
Publisher DOI: |
10.1016/j.yjmcc.2022.05.011 |
PubMed ID: |
35644481 |
Uncontrolled Keywords: |
Arrhythmia Calcium signaling Catecholaminergic polymorphic ventricular tachycardia Channelopathy Ryanodine receptor Sarcoplasmic reticulum calcium pump |
BORIS DOI: |
10.48350/170407 |
URI: |
https://boris.unibe.ch/id/eprint/170407 |
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