Suppression of ryanodine receptor function prolongs Ca2+ release refractoriness and promotes cardiac alternans in intact hearts

Zhong, Xiaowei; Sun, Bo; Vallmitjana, Alexander; Mi, Tao; Guo, Wenting; Ni, Mingke; Wang, Ruiwu; Guo, Ang; Duff, Henry J.; Gillis, Anne M.; Song, Long‐Sheng; Hove‐Madsen, Leif; Benítez, Raúl; Chen, S.R. Wayne Wayne

doi:10.1042/bcj20160606

Cited by 32 publications

(44 citation statements)

References 49 publications

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“…Finally, we found a reduction in RyR2 expression in AF ACMs (Supplemental Figure 8). Genetic suppression of RyR2 function prolongs Ca 2+ release refractoriness and promotes Ca 2+ release alternans in mouse hearts (41), suggesting that the RyR2 downregulation that we observed may also have contributed to the cellular phenotype.…”

Section: Discussionmentioning

confidence: 67%

Altered calcium handling produces reentry-promoting action potential alternans in atrial fibrillation–remodeled hearts

Liu¹,

Xiong²,

Qi³

et al. 2020

JCI Insight

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tivation might promote atrial alternans and arrhythmia susceptibility in patients with AF (11); however, there has been no direct demonstration.We speculated that abnormal Ca 2+ handling associated with AF might increase CTR and that Ca 2+ handling disturbances might not only predispose to abnormal Ca 2+ releases, causing spontaneous atrial ectopic activity, but also promote alternans behavior and susceptibility to reentry. We assessed this possibility in a dog model of electrically maintained AF, with a combination of cellular Ca 2+ imaging, simultaneous tissue optical Ca 2+ /transmembrane potential (Vm) optical mapping, and in vivo electrophysiology. Our results suggest that AF-associated Ca 2+ handling disturbances may be central not only to the trigger for reentry in terms of ectopic beat formation but also to the substrate for reentry through enhanced susceptibility to AP alternans. 2+ release restitution. Figure 1A shows representative recordings of cytosolic Ca 2+ transients (CaTs) at various S1-S2 coupling intervals from each group. AF prolonged CTR, which averaged 197 ± 13 ms in AF atrial cardiomyocytes (ACMs) versus 144 ± 7 ms in CTLs (P < 0.01; Figure 1B). Figure 1C shows typical CaT restitution curves, fitted by monoexponential relationships. AF increased the steepness of CaT restitution, decreasing the restitution time constant (τ) from 591 ± 18 ms in CTL ACMs to 315 ± 13 ms (P < 0.001; Figure 1D). Results AF-related changes in CTR and CaChanges in the threshold for cellular CaT alternans. It has long been recognized that changes in [Ca 2+ ] i are central to the development of repolarization alternans (12). Figure 2A shows cellular CaT recordings at progressively higher frequencies. In each case, beat-to-beat CaT alternans eventually appeared. The threshold frequency for alternans in each ACM in each group is shown in Figure 2B. The CaT alternans frequency threshold was significantly reduced, by 40%, in AF ACMs.Changes in CaT and sarcoplasmic reticulum Ca 2+ content. The results in Figure 1 and Figure 2 show that Ca 2+ release dynamics are altered in AF ACMs. To relate these changes in dynamics to basic Ca 2+ handling properties, we determined the effects of AF on CaT properties and sarcoplasmic reticulum (SR) Ca 2+ content under fixed-rate pacing. Supplemental Figure 1A (supplemental material available online with this article; https://doi.org/10.1172/jci.insight.133754DS1) shows representative CaT recordings. Diastolic [Ca 2+ ] i was increased, while CaT amplitude was significantly decreased, in AF ACMs (Supplemental Figure 1B). Changes in SR Ca 2+ content were assessed by simultaneously measuring caffeine-induced CaTs and sodium-calcium exchange (NCX) currents. Supplemental Figure 2A shows representative recordings of caffeine-induced CaTs and NCX currents from CTL and AF ACMs. AF significantly increased caffeine-induced NCX current amplitude and SR Ca 2+ content (Supplemental Figure 2, B and C) without affecting [Ca 2+ ] i decay kinetics (Supplemental Figure 2D).Changes in spontaneous Ca 2+ spar...

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Section: Discussionmentioning

confidence: 67%

Altered calcium handling produces reentry-promoting action potential alternans in atrial fibrillation–remodeled hearts

Liu¹,

Xiong²,

Qi³

et al. 2020

JCI Insight

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“…Often small changes in open probability of RyRs have significant physiological effects. Typical small changes are caused by suppression or gain-of-function mutations (Zhong et al, 2016) or calciumdependent regulation by calmodulin (Tripathy et al, 1995). Structural characterization of such fine regulation requires that RyR open probability observed in a cell membrane is accurately reproduced under cryo-EM conditions to allow capturing minor allosteric effects of the effectors on the channel conformation.…”

Section: Discussionmentioning

confidence: 99%

Influence of Lipid Mimetics on Gating of Ryanodine Receptor

Willegems

Efremov

2018

Structure

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Understanding gating principles of ion channels at high resolution is of great importance. Here we investigate the conformational transition from closed to open state in ryanodine receptor 1 (RyR1) reconstituted into lipid nanodiscs. RyR1 is a homotetrameric giant ion channel that couples excitation of muscle cells to fast calcium release from the sarcoplasmic reticulum. Using single-particle cryo-EM we show that RyR1 reconstituted into lipid nanodiscs is stabilized in the open conformation when bound to the plant toxin ryanodine, but not in the presence of its physiological activators, calcium and ATP. Further, using ryanodine binding assays we show that membrane mimetics influence RyR1 transition between closed and open-channel conformations. We find that all detergents, including fluorinated detergents added to nanodiscs, stabilize closed state of RyR1. Our biochemical results correlate with available structural data and suggest optimal conditions for structural studies of RyR1 gating.

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“…It is important to note that suppressed RyR2 activity has been shown to enhance cardiac alternans [35]. Furthermore, reduced RyR2 protein expression has been implicated in the genesis of cardiac alternans [21].…”

Section: Discussionmentioning

confidence: 99%

“…The following signal and image processing methods were implemented using MATLAB (The Mathworks Inc., Boston, MA) as described previously [34,35]. Briefly, Line-scan fluorescence images were filtered using a median filter applied iteratively a number of times according to an estimation of the image noise variance.…”

Section: Image and Signal Processingmentioning

confidence: 99%

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Reduced expression of cardiac ryanodine receptor protects against stress-induced ventricular tachyarrhythmia, but increases the susceptibility to cardiac alternans

Zhong

Vallmitjana

Sun

et al. 2018

Biochemical Journal

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Reduced protein expression of the cardiac ryanodine receptor type 2 (RyR2) is thought to affect the susceptibility to stress-induced ventricular tachyarrhythmia (VT) and cardiac alternans, but direct evidence for the role of RyR2 protein expression in VT and cardiac alternans is lacking. Here, we used a mouse model () that expresses a reduced level of the RyR2 protein to determine the impact of reduced RyR2 protein expression on the susceptibility to VT, cardiac alternans, cardiac hypertrophy, and sudden death. Electrocardiographic analysis revealed that after the injection of relatively high doses of caffeine and epinephrine (agents commonly used for stress test), wild-type (WT) mice displayed long-lasting VTs, whereas the mutant mice exhibited no VTs at all, indicating that the mutant mice are resistant to stress-induced VTs. Intact heart Ca imaging and action potential (AP) recordings showed that the mutant mice are more susceptible to fast-pacing induced Ca alternans and AP duration alternans compared with WT mice. The mutant mice also showed an increased heart-to-body-weight ratio and incidence of sudden death at young ages. Furthermore, the mutant hearts displayed altered Ca transients with increased time-to-peak and decay time (), increased ventricular wall thickness and ventricular cell area compared with WT hearts. These results indicate that reduced RyR2 protein expression suppresses stress-induced VTs, but enhances the susceptibility to cardiac alternans, hypertrophy, and sudden death.

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Suppression of ryanodine receptor function prolongs Ca2+ release refractoriness and promotes cardiac alternans in intact hearts

Cited by 32 publications

References 49 publications

Altered calcium handling produces reentry-promoting action potential alternans in atrial fibrillation–remodeled hearts

Altered calcium handling produces reentry-promoting action potential alternans in atrial fibrillation–remodeled hearts

Influence of Lipid Mimetics on Gating of Ryanodine Receptor

Reduced expression of cardiac ryanodine receptor protects against stress-induced ventricular tachyarrhythmia, but increases the susceptibility to cardiac alternans

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