Ryanodine receptor modification and regulation by intracellular Ca2+ and Mg2+ in healthy and failing human hearts

Walweel, Kafa; Molenaar, Peter; Imtiaz, Mohammad; Denniss, Amanda; Remedios, Cris dos; Helden, Dirk F. van; Dulhunty, Angela F.; Laver, Derek R.; Beard, Nicole A.

doi:10.1016/j.yjmcc.2017.01.016

Cited by 30 publications

(34 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 7 , 37 Recently, lipid bilayer experiments on RyR activity support these findings, with a major role for RyR phosphorylation and thiol oxidation in HF conditions. 21 In line with the study from Fischer et al , 7 no differences in response to CaMKII inhibition were found between myocytes from ischaemic and dilated cardiomyopathy (see Supplementary material online, Figure S12 ). The data complement earlier work on the global assessment of Ca 2+ transients in HF vs. non-HF human myocytes.…”

Section: Discussionsupporting

confidence: 81%

“…Indeed, previous studies have only reported on overall RyR activity recorded as sparks in diastole and in lipid bilayer experiments, without distinguishing subpopulations. 7 , 21 , 37 They mostly report an increase in total spark frequency, although Lindner et al 10 reported a decrease in HF. An important difference between the aforementioned study and ours is that we studied cells under voltage-clamp.…”

Section: Discussionmentioning

confidence: 99%

“… 10 Recent work studied RyRs extracted from left ventricular (LV) tissues samples from HF and non-HF and reconstituted in bilayers. 21 In the pig with MI, we reported that TATS remodelling affected properties of the RyR subpopulations but did not investigate the signalling mechanisms involved. 22 In a dog model of HF, Belevych et al 23 found that RyR subpopulations had different characteristics.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Hyperactive ryanodine receptors in human heart failure and ischaemic cardiomyopathy reside outside of couplons

Dries

Santiago

Gilbert

et al. 2018

Cardiovascular Research

View full text Add to dashboard Cite

AimsIn ventricular myocytes from humans and large mammals, the transverse and axial tubular system (TATS) network is less extensive than in rodents with consequently a greater proportion of ryanodine receptors (RyRs) not coupled to this membrane system. TATS remodelling in heart failure (HF) and after myocardial infarction (MI) increases the fraction of non-coupled RyRs. Here we investigate whether this remodelling alters the activity of coupled and non-coupled RyR sub-populations through changes in local signalling. We study myocytes from patients with end-stage HF, compared with non-failing (non-HF), and myocytes from pigs with MI and reduced left ventricular (LV) function, compared with sham intervention (SHAM).Methods and resultsSingle LV myocytes for functional studies were isolated according to standard protocols. Immunofluorescent staining visualized organization of TATS and RyRs. Ca2+ was measured by confocal imaging (fluo-4 as indicator) and using whole-cell patch-clamp (37°C). Spontaneous Ca2+ release events, Ca2+ sparks, as a readout for RyR activity were recorded during a 15 s period following conditioning stimulation at 2 Hz. Sparks were assigned to cell regions categorized as coupled or non-coupled sites according to a previously developed method. Human HF myocytes had more non-coupled sites and these had more spontaneous activity than in non-HF. Hyperactivity of these non-coupled RyRs was reduced by Ca2+/calmodulin-dependent kinase II (CaMKII) inhibition. Myocytes from MI pigs had similar changes compared with SHAM controls as seen in human HF myocytes. As well as by CaMKII inhibition, in MI, the increased activity of non-coupled sites was inhibited by mitochondrial reactive oxygen species (mito-ROS) scavenging. Under adrenergic stimulation, Ca2+ waves were more frequent and originated at non-coupled sites, generating larger Na+/Ca2+ exchange currents in MI than in SHAM. Inhibition of CaMKII or mito-ROS scavenging reduced spontaneous Ca2+ waves, and improved excitation–contraction coupling.ConclusionsIn HF and after MI, RyR microdomain re-organization enhances spontaneous Ca2+ release at non-coupled sites in a manner dependent on CaMKII activation and mito-ROS production. This specific modulation generates a substrate for arrhythmia that appears to be responsive to selective pharmacologic modulation.

show abstract

Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hyperactive ryanodine receptors in human heart failure and ischaemic cardiomyopathy reside outside of couplons

Dries

Santiago

Gilbert

et al. 2018

Cardiovascular Research

View full text Add to dashboard Cite

show abstract

“…58 This observation was expanded to other forms of cardiac disease, including HF, whereby elevated βAR signaling through PKA resulted in hyperphosphorylated S2808 and dissociation of FKBP12.6. 68, 69 These findings have not been universally observed by other investigators have catalyzed a number of follow-up studies which have introduced debate in the field. 70, 71 Some have argued that reduced Ca 2+ reuptake into the SR led is the predominant mechanism underlying HF 72 or that PLN activity and increased SR Ca 2+ load is involved.…”

Section: Arrhythmias Caused By Heritable Defects In Calcium-handling mentioning

confidence: 97%

Calcium Signaling and Cardiac Arrhythmias

Landstrom

Dobrev

Wehrens

2017

Circulation Research

433

331

View full text Add to dashboard Cite

There has been significant progress in our understanding of the molecular mechanisms by which calcium (Ca2+) ions mediate various types of cardiac arrhythmias. A growing list of inherited gene defects can cause potentially lethal cardiac arrhythmia syndromes, including catecholaminergic polymorphic ventricular tachycardia, congenital long QT syndrome, and hypertrophic cardiomyopathy. In addition, acquired deficits of multiple Ca2+-handling proteins can contribute to the pathogenesis of arrhythmias in patients with various types of heart disease. In this review article, we will first review the key role of Ca2+ in normal cardiac function - in particular, excitation-contraction coupling and normal electrical rhythms. The functional involvement of Ca2+ in distinct arrhythmia mechanisms will be discussed, followed by various inherited arrhythmia syndromes caused by mutations in Ca2+-handling proteins. Finally, we will discuss how changes in the expression of regulation of Ca2+ channels and transporters can cause acquired arrhythmias, and how these mechanisms might be targeted for therapeutic purposes.

show abstract

“…Interestingly, at this concentration, cardiac RyR2 channels incorporated into planar bilayers respond poorly to systolic concentrations of Ca 2+ ( 22 , 23 ). In the failing heart, RyR2 sensitivity to inhibition by cytosolic Mg 2+ is reduced when compared with healthy controls ( 24 ).…”

Section: Resultsmentioning

confidence: 99%

Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage

Reilly-O’Donnell

Robertson

Karumbi

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Aberrant Zn2+ homeostasis is associated with dysregulated intracellular Ca2+ release, resulting in chronic heart failure. In the failing heart a small population of cardiac ryanodine receptors (RyR2) displays sub-conductance-state gating leading to Ca2+ leakage from sarcoplasmic reticulum (SR) stores, which impairs cardiac contractility. Previous evidence suggests contribution of RyR2-independent Ca2+ leakage through an uncharacterized mechanism. We sought to examine the role of Zn2+ in shaping intracellular Ca2+ release in cardiac muscle. Cardiac SR vesicles prepared from sheep or mouse ventricular tissue were incorporated into phospholipid bilayers under voltage-clamp conditions, and the direct action of Zn2+ on RyR2 channel function was examined. Under diastolic conditions, the addition of pathophysiological concentrations of Zn2+ (≥2 nm) caused dysregulated RyR2-channel openings. Our data also revealed that RyR2 channels are not the only SR Ca2+-permeable channels regulated by Zn2+. Elevating the cytosolic Zn2+ concentration to 1 nm increased the activity of the transmembrane protein mitsugumin 23 (MG23). The current amplitude of the MG23 full-open state was consistent with that previously reported for RyR2 sub-conductance gating, suggesting that in heart failure in which Zn2+ levels are elevated, RyR2 channels do not gate in a sub-conductance state, but rather MG23-gating becomes more apparent. We also show that in H9C2 cells exposed to ischemic conditions, intracellular Zn2+ levels are elevated, coinciding with increased MG23 expression. In conclusion, these data suggest that dysregulated Zn2+ homeostasis alters the function of both RyR2 and MG23 and that both ion channels play a key role in diastolic SR Ca2+ leakage.

show abstract

Ryanodine receptor modification and regulation by intracellular Ca2+ and Mg2+ in healthy and failing human hearts

Abstract: Despite different aetiologies, disrupted RyR2 Ca sensitivity and biochemical modification of the channel are common constituents of failing heart RyR2 and may underlie the pathological disturbances in intracellular Ca signalling.

Cited by 30 publications

References 59 publications

Hyperactive ryanodine receptors in human heart failure and ischaemic cardiomyopathy reside outside of couplons

Hyperactive ryanodine receptors in human heart failure and ischaemic cardiomyopathy reside outside of couplons

Calcium Signaling and Cardiac Arrhythmias

Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage

Contact Info

Product

Resources

About