Uptake-leak balance of SR Ca2+ determines arrhythmogenic potential of RyR2R420Q+/− cardiomyocytes

Lopez, Ruben; Janíček, Radoslav; Fernández-Tenorio, Miguel; Courtehoux, Marianne; Matas, L; Gerbaud, Pascale; Gómez, Ana M.; Egger, Marcel; Niggli, Ernst

doi:10.1016/j.yjmcc.2022.05.011

Cited by 7 publications

(3 citation statements)

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“…It is not known why NPR-B +/− mice would exhibit elevated phosphorylation of RyR2 only at serine 2030; however, these findings are consistent with studies showing that serine 2030 is a major RyR2 PKA phosphorylation site 13 and that phosphorylation of RyR2 at serine 2030 can lead to spontaneous SR Ca 2+ release and triggered activity in mouse models of catecholaminergic polymorphic ventricular tachycardia. 43 There were no differences in I NCX between WT and NPR-B +/− mice. Thus, while NCX is responsible for Ca 2+ extrusion leading to SCaEs, changes in NCX activity do not contribute to the increase in SCaEs.…”

Section: Discussionmentioning

confidence: 90%

Natriuretic Peptide Receptor B Protects Against Atrial Fibrillation by Controlling Atrial cAMP Via Phosphodiesterase 2

Dorey,

Liu,

Jansen

et al. 2023

Circ: Arrhythmia and Electrophysiology

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BACKGROUND: β-AR (β-adrenergic receptor) stimulation regulates atrial electrophysiology and Ca 2+ homeostasis via cAMP-dependent mechanisms; however, enhanced β-AR signaling can promote atrial fibrillation (AF). CNP (C-type natriuretic peptide) can also regulate atrial electrophysiology through the activation of NPR-B (natriuretic peptide receptor B) and cGMP-dependent signaling. Nevertheless, the role of NPR-B in regulating atrial electrophysiology, Ca 2+ homeostasis, and atrial arrhythmogenesis is incompletely understood. METHODS: Studies were performed using atrial samples from human patients with AF or sinus rhythm and in wild-type and NPR-B-deficient (NPR-B +/− ) mice. Studies were conducted in anesthetized mice by intracardiac electrophysiology, in isolated mouse atrial preparations using high-resolution optical mapping, in isolated mouse and human atrial myocytes using patch-clamping and Ca 2+ imaging, and in mouse and human atrial tissues using molecular biology. RESULTS: Atrial NPR-B protein levels were reduced in patients with AF, and NPR-B +/− mice were more susceptible to AF. Atrial cGMP levels and PDE2 (phosphodiesterase 2) activity were reduced in NPR-B +/− mice leading to larger increases in atrial cAMP in the presence of the β-AR agonist isoproterenol. NPR-B +/− mice displayed larger increases in action potential duration and L-type Ca 2+ current in the presence of isoproterenol. This resulted in the occurrence of spontaneous sarcoplasmic reticulum Ca 2+ release events and delayed afterdepolarizations in NPR-B +/− atrial myocytes. Phosphorylation of the RyR2 (ryanodine receptor) and phospholamban was increased in NPR-B +/− atria in the presence of isoproterenol compared with the wildtypes. C-type natriuretic peptide inhibited isoproterenol-stimulated L-type Ca 2+ current through PDE2 in mouse and human atrial myocytes. CONCLUSIONS: NPR-B protects against AF by preventing enhanced atrial responses to β-adrenergic receptor agonists.

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Section: Discussionmentioning

confidence: 90%

Natriuretic Peptide Receptor B Protects Against Atrial Fibrillation by Controlling Atrial cAMP Via Phosphodiesterase 2

Dorey,

Liu,

Jansen

et al. 2023

Circ: Arrhythmia and Electrophysiology

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“…Furthermore the RyR2 is subject to control by an array of luminal proteins shown in figure 2. These include calsequestrin, junctin and triadin, as discussed in [6,[82][83][84].…”

Section: (B) the Role Of Sarcoplasmic Reticulum In Delayed Afterdepol...mentioning

confidence: 99%

Timing mechanisms to control heart rhythm and initiate arrhythmias: roles for intracellular organelles, signalling pathways and subsarcolemmal Ca²⁺

Terrar

2023

Phil. Trans. R. Soc. B

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Rhythms of electrical activity in all regions of the heart can be influenced by a variety of intracellular membrane bound organelles. This is true both for normal pacemaker activity and for abnormal rhythms including those caused by early and delayed afterdepolarizations under pathological conditions. The influence of the sarcoplasmic reticulum (SR) on cardiac electrical activity is widely recognized, but other intracellular organelles including lysosomes and mitochondria also contribute. Intracellular organelles can provide a timing mechanism (such as an SR clock driven by cyclic uptake and release of Ca 2+ , with an important influence of intraluminal Ca 2+ ), and/or can act as a Ca 2+ store involved in signalling mechanisms. Ca 2+ plays many diverse roles including carrying electric current, driving electrogenic sodium–calcium exchange (NCX) particularly when Ca 2+ is extruded across the surface membrane causing depolarization, and activation of enzymes which target organelles and surface membrane proteins. Heart function is also influenced by Ca 2+ mobilizing agents (cADP-ribose, nicotinic acid adenine dinucleotide phosphate and inositol trisphosphate) acting on intracellular organelles. Lysosomal Ca 2+ release exerts its effects via calcium/calmodulin-dependent protein kinase II to promote SR Ca 2+ uptake, and contributes to arrhythmias resulting from excessive beta-adrenoceptor stimulation. A separate arrhythmogenic mechanism involves lysosomes, mitochondria and SR. Interacting intracellular organelles, therefore, have profound effects on heart rhythms and NCX plays a central role. This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.

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“…Arrhythmias typically manifest during periods of increased sympathetic activity, which increases Ca 2+ entry and re-uptake pathways and shifts the SR towards greater operating Ca 2+ levels that greatly promotes spontaneous Ca 2+ release [ 102 ]. Ca 2+ release refractoriness, measured using the ratio of the second:first Ca 2+ spark occurring from the same CRU using a chemical modification of RyR2 with low concentration ryanodine [ 104 ], was reduced in a transgenic mouse model of the GoF CPVT-causing RyR2-R420Q +/− mutation under both basal and isoproterenol stimulation, indicating increased CICR sensitivity [ 105 ]. Reduced refractoriness was also observed in the same RyR2 CPVT model using two-photon photolysis of a caged Ca 2+ chelator [ 106 ] and in other models of GoF CPVT due to missense mutations (CSQ2-R33Q [ 107 ]) or knockout of CSQ2 [ 108 ].…”

Section: Arrhythmogenic Consequences Of Ryr2 Dysfunctionmentioning

confidence: 99%

Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease

Fowler

Zissimopoulos

2022

Biomolecules

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The ryanodine receptor (RyR2) has a critical role in controlling Ca2+ release from the sarcoplasmic reticulum (SR) throughout the cardiac cycle. RyR2 protein has multiple functional domains with specific roles, and four of these RyR2 protomers are required to form the quaternary structure that comprises the functional channel. Numerous mutations in the gene encoding RyR2 protein have been identified and many are linked to a wide spectrum of arrhythmic heart disease. Gain of function mutations (GoF) result in a hyperactive channel that causes excessive spontaneous SR Ca2+ release. This is the predominant cause of the inherited syndrome catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, rare hypoactive loss of function (LoF) mutations have been identified that produce atypical effects on cardiac Ca2+ handling that has been termed calcium release deficiency syndrome (CRDS). Aberrant Ca2+ release resulting from both GoF and LoF mutations can result in arrhythmias through the Na+/Ca2+ exchange mechanism. This mini-review discusses recent findings regarding the role of RyR2 domains and endogenous regulators that influence RyR2 gating normally and with GoF/LoF mutations. The arrhythmogenic consequences of GoF/LoF mutations will then be discussed at the macromolecular and cellular level.

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Uptake-leak balance of SR Ca2+ determines arrhythmogenic potential of RyR2R420Q+/− cardiomyocytes

Cited by 7 publications

References 50 publications

Natriuretic Peptide Receptor B Protects Against Atrial Fibrillation by Controlling Atrial cAMP Via Phosphodiesterase 2

Natriuretic Peptide Receptor B Protects Against Atrial Fibrillation by Controlling Atrial cAMP Via Phosphodiesterase 2

Timing mechanisms to control heart rhythm and initiate arrhythmias: roles for intracellular organelles, signalling pathways and subsarcolemmal Ca²⁺

Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease

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Uptake-leak balance of SR Ca2+ determines arrhythmogenic potential of RyR2R420Q+/− cardiomyocytes

Cited by 7 publications

References 50 publications

Natriuretic Peptide Receptor B Protects Against Atrial Fibrillation by Controlling Atrial cAMP Via Phosphodiesterase 2

Natriuretic Peptide Receptor B Protects Against Atrial Fibrillation by Controlling Atrial cAMP Via Phosphodiesterase 2

Timing mechanisms to control heart rhythm and initiate arrhythmias: roles for intracellular organelles, signalling pathways and subsarcolemmal Ca2+

Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease

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Timing mechanisms to control heart rhythm and initiate arrhythmias: roles for intracellular organelles, signalling pathways and subsarcolemmal Ca²⁺