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4. RyR2‐dependent modulation of neuronal hyperactivity: A potential therapeutic target for treating Alzheimer's disease.

Author

Yao, Jinjing and Chen, S. R. Wayne

Subjects
*ALZHEIMER'S disease, *RYANODINE receptors, *DENDRITIC spines, *MEMORY disorders, *GENETIC mutation
Abstract

Increasing evidence suggests that simply reducing β‐amyloid (Aβ) plaques may not significantly affect the progression of Alzheimer's disease (AD). There is also increasing evidence indicating that AD progression is driven by a vicious cycle of soluble Aβ‐induced neuronal hyperactivity. In support of this, it has recently been shown that genetically and pharmacologically limiting ryanodine receptor 2 (RyR2) open time prevents neuronal hyperactivity, memory impairment, dendritic spine loss and neuronal cell death in AD mouse models. By contrast, increased RyR2 open probability (Po) exacerbates the onset of familial AD‐associated neuronal dysfunction and induces AD‐like defects in the absence of AD‐causing gene mutations. Thus, RyR2‐dependent modulation of neuronal hyperactivity represents a promising new target for combating AD. [ABSTRACT FROM AUTHOR]

Published
2024
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10. De novo ITPR1 variants are a recurrent cause of early-onset ataxia, acting via loss of channel function

Author

Synofzik, Matthis, Helbig, Katherine L., Harmuth, Florian, Deconinck, Tine, Tanpaiboon, Pranoot, Sun, Bo, Guo, Wenting, Wang, Ruiwu, Palmaer, Erika, Tang, Sha, Schaefer, G. Bradley, Gburek-Augustat, Janina, Züchner, Stephan, Krägeloh-Mann, Ingeborg, Baets, Jonathan, de Jonghe, Peter, Bauer, Peter, Chen, S. R. Wayne, Schöls, Ludger, and Schüle, Rebecca

Published
2018
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12. RyR2 Serine-2030 PKA Site Governs Ca2+Release Termination and Ca2+Alternans

Author

Wei, Jinhong, Guo, Wenting, Wang, Ruiwu, Estillore, John Paul, Belke, Darrell, Chen, Yong-Xiang, Vallmitjana, Alexander, Benítez, Raul, Hove-Madsen, Leif, Chen, S. R. Wayne, Wei, Jinhong, Guo, Wenting, Wang, Ruiwu, Estillore, John Paul, Belke, Darrell, Chen, Yong-Xiang, Vallmitjana, Alexander, Benítez, Raul, Hove-Madsen, Leif, and Chen, S. R. Wayne

Abstract

Background: PKA (protein kinase A)-mediated phosphorylation of cardiac RyR2 (ryanodine receptor 2) has been extensively studied for decades, but the physiological significance of PKA phosphorylation of RyR2 remains poorly understood. Recent determination of high-resolution 3-dimensional structure of RyR2 in complex with CaM (calmodulin) reveals that the major PKA phosphorylation site in RyR2, serine-2030 (S2030), is located within a structural pathway of CaM-dependent inactivation of RyR2. This novel structural insight points to a possible role of PKA phosphorylation of RyR2 in CaM-dependent inactivation of RyR2, which underlies the termination of Ca2+ release and induction of cardiac Ca2+ alternans. Methods: We performed single-cell endoplasmic reticulum Ca2+ imaging to assess the impact of S2030 mutations on Ca2+ release termination in human embryonic kidney 293 cells. Here we determined the role of the PKA site RyR2-S2030 in a physiological setting, we generated a novel mouse model harboring the S2030L mutation and carried out confocal Ca2+ imaging. Results: We found that mutations, S2030D, S2030G, S2030L, S2030V, and S2030W reduced the endoplasmic reticulum luminal Ca2+ level at which Ca2+ release terminates (the termination threshold), whereas S2030P and S2030R increased the termination threshold. S2030A and S2030T had no significant impact on release termination. Furthermore, CaM-wild-type increased, whereas Ca2+ binding deficient CaM mutant (CaM-M [a loss-of-function CaM mutation with all 4 EF-hand motifs mutated]), PKA, and Ca2+/CaMKII (CaM-dependent protein kinase II) reduced the termination threshold. The S2030L mutation abolished the actions of CaM-wild-type, CaM-M, and PKA, but not CaMKII, in Ca2+ release termination. Moreover, we showed that isoproterenol and CaM-M suppressed pacing-induced Ca2+ alternans and accelerated Ca2+ transient recovery in intact working hearts, whereas CaM-wild-type exerted an opposite effect. The impact of isoproterenol was pa

Published
2023

13. Supplementary Material Beta-blocker treatment of patients with atrial fibrillation attenuates spontaneous calcium release-induced electrical activity

Author

Jiménez-Sábado, Verónica [0000-0001-7720-988X], Jiménez-Sábado, Verónica, Casabella, Sergi, Llach, Anna, Gich, Ignasi, Casellas, Sergi, Ciruela, Francisco, Chen, S. R. Wayne, Guerra Ramos, José María, Ginel, Antonino, Benítez, Raul, Cinca, Juan, Tarifa, Carmen, Hove-Madsen, Leif, Jiménez-Sábado, Verónica [0000-0001-7720-988X], Jiménez-Sábado, Verónica, Casabella, Sergi, Llach, Anna, Gich, Ignasi, Casellas, Sergi, Ciruela, Francisco, Chen, S. R. Wayne, Guerra Ramos, José María, Ginel, Antonino, Benítez, Raul, Cinca, Juan, Tarifa, Carmen, and Hove-Madsen, Leif

Published
2023

14. Increased Ca2+ Transient Underlies RyR2-Related Left Ventricular Noncompaction

Author

Ni, Mingke, Li, Yanhui, Wei, Jinhong, Song, Zhenpeng, Wang, Hui, Yao, Jinjing, Chen, Yong-Xiang, Belke, Darrell, Estillore, John Paul, Wang, Ruiwu, Vallmitjana, Alexander, Benitez, Raul, Hove-Madsen, Leif, Feng, Wei, Chen, Ju, Roston, Thomas M., Sanatani, Shubhayan, Lehman, Anna, Chen, S. R. Wayne, Ni, Mingke, Li, Yanhui, Wei, Jinhong, Song, Zhenpeng, Wang, Hui, Yao, Jinjing, Chen, Yong-Xiang, Belke, Darrell, Estillore, John Paul, Wang, Ruiwu, Vallmitjana, Alexander, Benitez, Raul, Hove-Madsen, Leif, Feng, Wei, Chen, Ju, Roston, Thomas M., Sanatani, Shubhayan, Lehman, Anna, and Chen, S. R. Wayne

Abstract

A loss-of-function cardiac ryanodine receptor (RyR2) mutation, I4855M+/-, has recently been linked to a new cardiac disorder termed RyR2 Ca2+ release deficiency syndrome (CRDS) as well as left ventricular noncompaction (LVNC). The mechanism by which RyR2 loss-of-function causes CRDS has been extensively studied, but the mechanism underlying RyR2 loss-of-function-associated LVNC is unknown. Here, we determined the impact of a CRDS-LVNC-associated RyR2-I4855M+/- loss-of-function mutation on cardiac structure and function.

Published
2023

17. Cardiac Ryanodine Receptor (Ryr2)-mediated Calcium Signals Specifically Promote Glucose Oxidation via Pyruvate Dehydrogenase

Author

Bround, Michael J., Wambolt, Rich, Cen, Haoning, Asghari, Parisa, Albu, Razvan F., Han, Jun, McAfee, Donald, Pourrier, Marc, Scott, Nichollas E., Bohunek, Lubos, Kulpa, Jerzy E., Chen, S. R. Wayne, Fedida, David, Brownsey, Roger W., Borchers, Christoph H., Foster, Leonard J., Mayor, Thibault, Moore, Edwin D.W., Allard, Michael F., and Johnson, James D.

Published
2016
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23. RyR2 C-terminal truncating variants identified in patients with arrhythmic phenotypes exert a dominant negative effect through formation of wildtype-truncation heteromers.

Author

Shanshan Tian, Xiaowei Zhong, Hui Wang, Jinhong Wei, Wenting Guo, Ruiwu Wang, Estillore, John Paul, Napolitano, Carlo, Duff, Henry H., Ilhan, Erkan, Knight, Linda M., Lloyd, Michael S., Roberts, Jason D., Priori, Silvia G., and Chen, S. R. Wayne

Subjects
RYANODINE receptors, CARDIAC arrest, GENETIC testing, VENTRICULAR arrhythmia, GENE expression, VENTRICULAR tachycardia
Abstract

Gain-of-function missense variants in the cardiac ryanodine receptor (RyR2) are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), whereas RyR2 loss-offunction missense variants cause Ca2+ release deficiency syndrome (CRDS). Recently, truncating variants in RyR2 have also been associated with ventricular arrhythmias (VAs) and sudden cardiac death. However, there are limited insights into the potential clinical relevance and in vitro functional impact of RyR2 truncating variants. We performed genetic screening of patients presenting with syncope, VAs, or unexplained sudden death and in vitro characterization of the expression and function of RyR2 truncating variants in HEK293 cells. We identified two previously unknown RyR2 truncating variants (Y4591Ter and R4663Ter) and one splice site variant predicted to result in a frameshift and premature termination (N4717 + 15Ter). These 3 new RyR2 truncating variants and a recently reported RyR2 truncating variant, R4790Ter, were generated and functionally characterized in vitro. Immunoprecipitation and immunoblotting analyses showed that all 4 RyR2 truncating variants formed heteromers with the RyR2-wildtype (WT) protein. Each of these C-terminal RyR2 truncations was non-functional and suppressed [3H]ryanodine binding to RyR2-WT and RyR2-WT mediated store overload induced spontaneous Ca2+ release activity in HEK293 cells. The expression of these RyR2 truncating variants in HEK293 cells was markedly reduced compared with that of the full-length RyR2 WT protein. Our data indicate that C-terminal RyR2 truncating variants are non-functional and can exert a dominant negative impact on the function of the RyR2 WT protein through formation of heteromeric WT/truncation complex. [ABSTRACT FROM AUTHOR]

Published
2023
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25. Impact of R-Carvedilol on β2-Adrenergic Receptor-Mediated Spontaneous Calcium Release in Human Atrial Myocytes

Author

Casabella-Ramón, Sergi, primary, Jiménez-Sábado, Verónica, additional, Tarifa, Carmen, additional, Casellas, Sandra, additional, Lu, Tien Tina, additional, Izquierdo-Castro, Paloma, additional, Gich, Ignasi, additional, Jiménez, Marcel, additional, Ginel, Antonino, additional, Guerra, José M., additional, Chen, S. R. Wayne, additional, Benítez, Raul, additional, and Hove-Madsen, Leif, additional

Published
2022
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26. FoxP3-mediated blockage of ryanodine receptor 2 is the molecular basis for the contact-based suppression by regulatory T cells

Author

Wang, Xiaobo, primary, Geng, Shuang, additional, Meng, Junchen, additional, Kang, Ning, additional, Liu, Xinyi, additional, Xu, Yanni, additional, Lv, Huiyun, additional, Xu, Ying, additional, Xu, Xun, additional, Song, Xinrong, additional, Zhang, Bin, additional, Wang, Xin, additional, Nuerbulati, Nuerdida, additional, Zhang, Ze, additional, Zhai, Di, additional, Mao, Xin, additional, Sun, Ruya, additional, Wang, Xiaoting, additional, Wang, Ruiwu, additional, Guo, Jie, additional, Chen, S. R. Wayne, additional, Zhou, Xuyu, additional, Xia, Tie, additional, Qi, Hai, additional, Hu, Xiaoyu, additional, and Shi, Yan, additional

Published
2022
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29. Clinical and Functional Characterization of Ryanodine Receptor 2 Variants Implicated in Calcium-Release Deficiency Syndrome

Author

Roston, Thomas M., primary, Wei, Jinhong, additional, Guo, Wenting, additional, Li, Yanhui, additional, Zhong, Xiaowei, additional, Wang, Ruiwu, additional, Estillore, John Paul, additional, Peltenburg, Puck J., additional, Noguer, Ferran Rosés I., additional, Till, Jan, additional, Eckhardt, Lee L., additional, Orland, Kate M., additional, Hamilton, Robert, additional, LaPage, Martin J., additional, Krahn, Andrew D., additional, Tadros, Rafik, additional, Vinocur, Jeffrey M., additional, Kallas, Dania, additional, Franciosi, Sonia, additional, Roberts, Jason D., additional, Wilde, Arthur A. M., additional, Jensen, Henrik K., additional, Sanatani, Shubhayan, additional, and Chen, S. R. Wayne, additional

Published
2022
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30. The ryanodine receptor store-sensing gate controls C[a.sup.2+] waves and C[a.sup.2+]-triggered arrhythmias

Author

Chen, Wenqian, Wang, Ruiwu, Chen, Biyi, Zhong, Xiaowei, Kong, Huihui, Bai, Yunlong, Xie, Cuihong, Zhang, Jingqun, Guo, Ang, Tian, Xixi, Jones, Peter P., 'Mara, Megan L., Liu, Yingjie, Mi, Tao, Zhang, Lin, Bolstad, Jeff, Semeniuk, Lisa, Cheng, Hongqiang, Zhang, Jianlin, Chen, Ju, Tieleman, D. Peter, Gillis, Anne M., Duff, Henry J., Fill, Michael, Song, Long-Sheng, and Chen, S. R. Wayne

Subjects
Medical research, Medicine, Experimental, Arrhythmia -- Research, Biological sciences, Health
Abstract

Spontaneous C[a.sup.2+] release from intracellular stores is important for various physiological and pathological processes. In cardiac muscle cells, spontaneous store overload-induced C[a.sup.2+] release (SOICR) can result in C[a.sup.2+] waves, a [...]

Published
2014

31. Using hiPSC‐CMs to Examine Mechanisms of Catecholaminergic Polymorphic Ventricular Tachycardia

Author

Arslanova, Alia, primary, Shafaattalab, Sanam, additional, Ye, Kevin, additional, Asghari, Parisa, additional, Lin, Lisa, additional, Kim, BaRun, additional, Roston, Thomas M., additional, Hove‐Madsen, Leif, additional, Van Petegem, Filip, additional, Sanatani, Shubhayan, additional, Moore, Edwin, additional, Lynn, Francis, additional, Søndergaard, Mads, additional, Luo, Yonglun, additional, Chen, S. R. Wayne, additional, and Tibbits, Glen F., additional

Published
2021
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32. β2‐adrenergic stimulation potentiates spontaneous calcium release by increasing signal mass and co‐activation of ryanodine receptor clusters

Author

Nolla‐Colomer, Carme, primary, Casabella‐Ramon, Sergi, additional, Jimenez‐Sabado, Veronica, additional, Vallmitjana, Alexander, additional, Tarifa, Carmen, additional, Herraiz‐Martínez, Adela, additional, Llach, Anna, additional, Tauron, Manel, additional, Montiel, Jose, additional, Cinca, Juan, additional, Chen, S. R. Wayne, additional, Benitez, Raul, additional, and Hove‐Madsen, Leif, additional

Published
2021
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33. R-carvedilol, a potential new therapy for Alzheimer's disease.

Author

Jinjing Yao and Chen, S. R. Wayne

Subjects
ALZHEIMER'S disease, AMYLOID plaque, RYANODINE receptors, MEMORY disorders
Abstract

For decades, the amyloid cascade hypothesis has been the leading hypothesis in studying Alzheimer's disease (AD) pathology and drug development. However, a growing body of evidence indicates that simply removing amyloid plaques may not significantly affect AD progression. Alternatively, it has been proposed that AD progression is driven by increased neuronal excitability. Consistent with this alternative hypothesis, recent studies showed that pharmacologically limiting ryanodine receptor 2 (RyR2) open time with the R-carvedilol enantiomer prevented and reversed neuronal hyperactivity, memory impairment, and neuron loss in AD mouse models without affecting the accumulation of ß-amyloid (Aβ). These data indicate that R-carvedilol could be a potential new therapy for AD. [ABSTRACT FROM AUTHOR]

Published
2022
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35. Using hiPSC-CMs to Examine Mechanisms of Catecholaminergic Polymorphic Ventricular Tachycardia

Author

Arslanova, Alia, Shafaattalab, Sanam, Ye, Kevin, Asghari, Parisa, Lin, Lisa, Kim, BaRun, Roston, Thomas M., Hove-Madsen, Leif, Petegem, Filip van, Sanatani, Shubhayan, Moore, Edwin, Lynn, Francis C., Søndergaard, Mads, Luo, Yonglun, Chen, S. R. Wayne, Tibbits, Glen F., Stem Cell Network, Canadian Institutes of Health Research, and BC Children's Hospital Foundation

Subjects
Sudden cardiac death, Ryanodine receptor, Catecholaminergic polymorphic ventricular tachycardia, Inherited arrhythmia, Human induced pluripotent stem cells, Diseasemodeling
Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal inherited cardiac arrhythmia condition, triggered by physical or acute emotional stress, that predominantly expresses early in life. Gain-of-function mutations in the cardiac ryanodine receptor gene (RYR2) account for the majority of CPVT cases, causing substantial disruption of intracellular calcium (Ca) homeostasis particularly during the periods of β-adrenergic receptor stimulation. However, the highly variable penetrance, patient outcomes, and drug responses observed in clinical practice remain unexplained, even for patients with well-established founder RyR2 mutations. Therefore, investigation of the electrophysiological consequences of CPVT-causing RyR2 mutations is crucial to better understand the pathophysiology of the disease. The development of strategies for reprogramming human somatic cells to human induced pluripotent stem cells (hiPSCs) has provided a unique opportunity to study inherited arrhythmias, due to the ability of hiPSCs to differentiate down a cardiac lineage. Employment of genome editing enables generation of disease-specific cell lines from healthy and diseased patient-derived hiPSCs, which subsequently can be differentiated into cardiomyocytes. This paper describes the means for establishing an hiPSC-based model of CPVT in order to recapitulate the disease phenotype in vitro and investigate underlying pathophysiological mechanisms. The framework of this approach has the potential to contribute to disease modeling and personalized medicine using hiPSC-derived cardiomyocytes. © 2021 Wiley Periodicals LLC. The authors gratefully acknowledge financial support from the Stem Cell Network(FY21/ACCT2-13 to GFT); the Canadian Institutes of Health Research Institute of Circulatory and Respiratory Health (GR020601 toGFT and FVP); and the Mining for Miraclesfund raising on behalf of the BC Children’s Hospital Foundation (to G.F.T., S.S., and F.L.).

Published
2021

36. Ca 2+-CaM Dependent Inactivation of RyR2 Underlies Ca 2+ Alternans in Intact Heart

Author

Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundació La Marató de TV3, Generalitat de Catalunya, Wei, Jinhong, Yao, Jinjing, Belke, Darrell, Guo, Wenting, Zhong, Xiaowei, Sun, Bo, Wang, Ruiwu, Estillore, John Paul, Vallmitjana, Alexander, Benítez, Raul, Hove-Madsen, Leif, Alvarez Lacalle, Enrique, Echebarria, Blas, Chen, S. R. Wayne, Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundació La Marató de TV3, Generalitat de Catalunya, Wei, Jinhong, Yao, Jinjing, Belke, Darrell, Guo, Wenting, Zhong, Xiaowei, Sun, Bo, Wang, Ruiwu, Estillore, John Paul, Vallmitjana, Alexander, Benítez, Raul, Hove-Madsen, Leif, Alvarez Lacalle, Enrique, Echebarria, Blas, and Chen, S. R. Wayne

Abstract

Rationale: Ca2+ alternans plays an essential role in cardiac alternans that can lead to ventricular fibrillation, but the mechanism underlying Ca2+ alternans remains undefined. Increasing evidence suggests that Ca2+ alternans results from alternations in the inactivation of cardiac RyR2 (ryanodine receptor 2). However, what inactivates RyR2 and how RyR2 inactivation leads to Ca2+ alternans are unknown. Objective: To determine the role of CaM (calmodulin) on Ca2+ alternans in intact working mouse hearts. Methods and results: We used an in vivo local gene delivery approach to alter CaM function by directly injecting adenoviruses expressing CaM-wild type, a loss-of-function CaM mutation, CaM (1-4), and a gain-of-function mutation, CaM-M37Q, into the anterior wall of the left ventricle of RyR2 wild type or mutant mouse hearts. We monitored Ca2+ transients in ventricular myocytes near the adenovirus-injection sites in Langendorff-perfused intact working hearts using confocal Ca2+ imaging. We found that CaM-wild type and CaM-M37Q promoted Ca2+ alternans and prolonged Ca2+ transient recovery in intact RyR2 wild type and mutant hearts, whereas CaM (1-4) exerted opposite effects. Altered CaM function also affected the recovery from inactivation of the L-type Ca2+ current but had no significant impact on sarcoplasmic reticulum Ca2+ content. Furthermore, we developed a novel numerical myocyte model of Ca2+ alternans that incorporates Ca2+-CaM-dependent regulation of RyR2 and the L-type Ca2+ channel. Remarkably, the new model recapitulates the impact on Ca2+ alternans of altered CaM and RyR2 functions under 9 different experimental conditions. Our simulations reveal that diastolic cytosolic Ca2+ elevation as a result of rapid pacing triggers Ca2+-CaM dependent inactivation of RyR2. The resultant RyR2 inactivation diminishes sarcoplasmic reticulum Ca2+ release, which, in turn, reduces diastolic cytosolic Ca2+, leading to alternations in diastolic cytosolic Ca2+, RyR2 inactivatio

Published
2021

37. Cardiac ryanodine receptor calcium release deficiency syndrome

Author

Canadian Institutes of Health Research, National Natural Science Foundation of China, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundació La Marató de TV3, Royal Netherlands Academy of Arts and Sciences, European Research Council, Novo Nordisk Foundation, National Institutes of Health (US), Alberta Innovates Health Solutions, University of Calgary, Heart and Stroke Foundation of Canada, Sun, Bo, Yao, Jinjing, Ni, Mingke, Wei, Jinhong, Zhong, Xiaowei, Guo, Wenting, Zhang, Lin, Wang, Ruiwu, Belke, Darrell, Chen, Yong-Xiang, Lieve, Krystien V. V., Broendberg, Anders K., Roston, Thomas M., Blankoff, Ivan, Kammeraad, Janneke A., Alvensleben, Johannes C. von, Lazarte, Julieta, Vallmitjana, Alexander, Bohne, Loryn J., Rose, Robert A., Benítez, Raul, Hove-Madsen, Leif, Napolitano, Carlo, Hegele, Robert A., Fill, Michael, Sanatani, Shubhayan, Wilde, Arthur A.M., Roberts, Jason D., Priori, Silvia G., Jensen, Henrik K., Chen, S. R. Wayne, Canadian Institutes of Health Research, National Natural Science Foundation of China, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundació La Marató de TV3, Royal Netherlands Academy of Arts and Sciences, European Research Council, Novo Nordisk Foundation, National Institutes of Health (US), Alberta Innovates Health Solutions, University of Calgary, Heart and Stroke Foundation of Canada, Sun, Bo, Yao, Jinjing, Ni, Mingke, Wei, Jinhong, Zhong, Xiaowei, Guo, Wenting, Zhang, Lin, Wang, Ruiwu, Belke, Darrell, Chen, Yong-Xiang, Lieve, Krystien V. V., Broendberg, Anders K., Roston, Thomas M., Blankoff, Ivan, Kammeraad, Janneke A., Alvensleben, Johannes C. von, Lazarte, Julieta, Vallmitjana, Alexander, Bohne, Loryn J., Rose, Robert A., Benítez, Raul, Hove-Madsen, Leif, Napolitano, Carlo, Hegele, Robert A., Fill, Michael, Sanatani, Shubhayan, Wilde, Arthur A.M., Roberts, Jason D., Priori, Silvia G., Jensen, Henrik K., and Chen, S. R. Wayne

Abstract

Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia, a condition characterized by prominent ventricular ectopy in response to catecholamine stress, which can be reproduced on exercise stress testing (EST). However, reports of sudden cardiac death (SCD) have emerged in EST-negative individuals who have loss-of-function (LOF) RyR2 mutations. The clinical relevance of RyR2 LOF mutations including their pathogenic mechanism, diagnosis, and treatment are all unknowns. Here, we performed clinical and genetic evaluations of individuals who suffered from SCD and harbored an LOF RyR2 mutation. We carried out electrophysiological studies using a programed electrical stimulation protocol consisting of a long-burst, long-pause, and short-coupled (LBLPS) ventricular extra-stimulus. Linkage analysis of RyR2 LOF mutations in six families revealed a combined logarithm of the odds ratio for linkage score of 11.479 for a condition associated with SCD with negative EST. A RyR2 LOF mouse model exhibited no catecholamine-provoked ventricular arrhythmias as in humans but did have substantial cardiac electrophysiological remodeling and an increased propensity for early afterdepolarizations. The LBLPS pacing protocol reliably induced ventricular arrhythmias in mice and humans having RyR2 LOF mutations, whose phenotype is otherwise concealed before SCD. Furthermore, treatment with quinidine and flecainide abolished LBLPS-induced ventricular arrhythmias in model mice. Thus, RyR2 LOF mutations underlie a previously unknown disease entity characterized by SCD with normal EST that we have termed RyR2 Ca2+ release deficiency syndrome (CRDS). Our study provides insights into the mechanism of CRDS, reports a specific CRDS diagnostic test, and identifies potentially efficacious anti-CRDS therapies.

Published
2021

45. Cardiac ryanodine receptor calcium release deficiency syndrome

Author

Sun, Bo, primary, Yao, Jinjing, additional, Ni, Mingke, additional, Wei, Jinhong, additional, Zhong, Xiaowei, additional, Guo, Wenting, additional, Zhang, Lin, additional, Wang, Ruiwu, additional, Belke, Darrell, additional, Chen, Yong-Xiang, additional, Lieve, Krystien V.V., additional, Broendberg, Anders K., additional, Roston, Thomas M., additional, Blankoff, Ivan, additional, Kammeraad, Janneke A., additional, von Alvensleben, Johannes C., additional, Lazarte, Julieta, additional, Vallmitjana, Alexander, additional, Bohne, Loryn J., additional, Rose, Robert A., additional, Benitez, Raul, additional, Hove-Madsen, Leif, additional, Napolitano, Carlo, additional, Hegele, Robert A., additional, Fill, Michael, additional, Sanatani, Shubhayan, additional, Wilde, Arthur A.M., additional, Roberts, Jason D., additional, Priori, Silvia G., additional, Jensen, Henrik K., additional, and Chen, S. R. Wayne, additional

Published
2021
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47. β2‐adrenergic stimulation potentiates spontaneous calcium release by increasing signal mass and co‐activation of ryanodine receptor clusters.

Author

Nolla‐Colomer, Carme, Casabella‐Ramon, Sergi, Jimenez‐Sabado, Veronica, Vallmitjana, Alexander, Tarifa, Carmen, Herraiz‐Martínez, Adela, Llach, Anna, Tauron, Manel, Montiel, Jose, Cinca, Juan, Chen, S. R. Wayne, Benitez, Raul, and Hove‐Madsen, Leif

Subjects
RYANODINE receptors, GREEN fluorescent protein, CALCIUM, ATRIAL fibrillation
Abstract

Aims: It is unknown how β‐adrenergic stimulation affects calcium dynamics in individual RyR2 clusters and leads to the induction of spontaneous calcium waves. To address this, we analysed spontaneous calcium release events in green fluorescent protein (GFP)‐tagged RyR2 clusters. Methods: Cardiomyocytes from mice with GFP‐tagged RyR2 or human right atrial tissue were subjected to immunofluorescent labelling or confocal calcium imaging. Results: Spontaneous calcium release from single RyR2 clusters induced 91.4% ± 2.0% of all calcium sparks while 8.0% ± 1.6% were caused by release from two neighbouring clusters. Sparks with two RyR2 clusters had 40% bigger amplitude, were 26% wider, and lasted 35% longer at half maximum. Consequently, the spark mass was larger in two‐ than one‐cluster sparks with a median and interquartile range for the cumulative distribution of 15.7 ± 20.1 vs 7.6 ± 5.7 a.u. (P <.01). β2‐adrenergic stimulation increased RyR2 phosphorylation at s2809 and s2815, tripled the fraction of two‐ and three‐cluster sparks, and significantly increased the spark mass. Interestingly, the amplitude and mass of the calcium released from a RyR2 cluster were proportional to the SR calcium load, but the firing rate was not. The spark mass was also higher in 33 patients with atrial fibrillation than in 36 without (22.9 ± 23.4 a.u. vs 10.7 ± 10.9; P =.015). Conclusions: Most sparks are caused by activation of a single RyR2 cluster at baseline while β‐adrenergic stimulation doubles the mass and the number of clusters per spark. This mimics the shift in the cumulative spark mass distribution observed in myocytes from patients with atrial fibrillation. [ABSTRACT FROM AUTHOR]

Published
2022
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48. Tracheopathia Osteoplastica

Author

Raj, Satish R., primary, Chen, S. R. Wayne, additional, Sheldon, Robert S., additional, Shah, Arti N., additional, Kantharia, Bharat K., additional, Salzer, Ulrich, additional, Grimbacher, Bodo, additional, Leung, Alexander K. C., additional, Kamat, Deepak, additional, Kolovou, Genovefa D., additional, Anagnostopoulou, Katherine K., additional, Cokkinos, Dennis V., additional, Shinkai, Takahiro, additional, Quinlivan, Rosaline C. M., additional, Beynon, Robert, additional, Kolter, Thomas, additional, Schepers, Ute, additional, Sandhoff, Konrad, additional, Nicot, Christophe, additional, Kempf, Werner, additional, Dummer, Reinhard, additional, Burg, Günter, additional, Geisthoff, Urban W., additional, Bartholdi, Deborah, additional, Schinzel, Albert, additional, Bornstein, Stefan R., additional, Blau, Nenad, additional, Goldmuntz, Elizabeth, additional, Schnog, John-John B., additional, Gerdes, Victor E. A., additional, Bonaventure, Jacky, additional, Nohr, Donatus, additional, Marinaki, Anthony M., additional, Arenas, Monica, additional, Groff IV, Robert F., additional, Huang, Jason H., additional, Cate, Hugo Ten, additional, Tefferi, Ayalew, additional, Tsai, Han-Mou, additional, Ibraheim, Mofid, additional, Ikomi, Amaj, additional, Olsson, Bob, additional, Wadenvik, Hans, additional, Ilcheff, Julian, additional, Bounameaux, Henri, additional, Righini, Marc, additional, Boos, Christopher J., additional, Lip, Gregory Y. H., additional, Ramot, Yuval, additional, Goldschmidt, Neta, additional, Nyska, Abraham, additional, Van Kuilenburg, André B. P., additional, Van Gennip*, Albert H., additional, Koch, Christian A., additional, Sarlis, Nicholas J., additional, Forrest, Douglas, additional, Kopp, Peter, additional, Sancak, Seda, additional, Eszlinger, Markus, additional, Paschke, Ralf, additional, Fioravanti, Antonella, additional, Mazzei, Maria Antonietta, additional, Coppola, Giuseppina, additional, Volterrani, Luca, additional, Zenner, Hans-Peter, additional, Zalaman, Ilse Maria, additional, Schumacher, Ulrike, additional, Autenrieth, Ingo B., additional, Wadhani, Nitin, additional, Red, Hari, additional, Azmoon, Shah, additional, Singh, Harpreet, additional, Singh, Bramah N., additional, Brown, David W., additional, Geva, Tal, additional, Guarneri, Claudio, additional, Borgia, Francesco, additional, Vaccaro, Mario, additional, Müller, Norbert, additional, Kohlhase, Jürgen, additional, Erhardt, Andreas, additional, Mboti, Freddy, additional, Yazdanbakhsh, Karina, additional, Sutton, Millicent, additional, Hillebrands, Jan-Luuk, additional, de Weger, Roel, additional, Rozing, Jan, additional, Leatherbury, Linda, additional, Lo, Cecilia, additional, Engel, Jutta, additional, Louis, Elan D., additional, Guarneri, Fabrizio, additional, Berneburg, Mark, additional, Schwarz, Thomas, additional, Krombach, Gabriele A., additional, Baldi, Alfonso, additional, Niwa, Koichiro, additional, Guran, Sefik, additional, Pugh, Trevor J., additional, Marra, Marco A., additional, Wolstenholme, John, additional, Hegde, Hardally R., additional, Richter, Joachim, additional, Yamagishi, Hiroyuki, additional, Fukuda, Keiichi, additional, Ledochowski, Maximilian, additional, Fuchs, Dietmar, additional, Agrawal, Pushpa, additional, Alam†, Md. Suhail, additional, Garg†, Saurabh K., additional, Wienecke, Ralf, additional, Capasso, Giovambattista, additional, Bernardi, Mauro, additional, Trevisani, Franco, additional, Nakamura, Kimitoshi, additional, Matsumoto, Shiro, additional, Mitsubuchi, Hiroshi, additional, and Endo, Fumio, additional

Published
2009
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49. Tremor, Essential

Author

Raj, Satish R., primary, Chen, S. R. Wayne, additional, Sheldon, Robert S., additional, Shah, Arti N., additional, Kantharia, Bharat K., additional, Salzer, Ulrich, additional, Grimbacher, Bodo, additional, Leung, Alexander K. C., additional, Kamat, Deepak, additional, Kolovou, Genovefa D., additional, Anagnostopoulou, Katherine K., additional, Cokkinos, Dennis V., additional, Shinkai, Takahiro, additional, Quinlivan, Rosaline C. M., additional, Beynon, Robert, additional, Kolter, Thomas, additional, Schepers, Ute, additional, Sandhoff, Konrad, additional, Nicot, Christophe, additional, Kempf, Werner, additional, Dummer, Reinhard, additional, Burg, Günter, additional, Geisthoff, Urban W., additional, Bartholdi, Deborah, additional, Schinzel, Albert, additional, Bornstein, Stefan R., additional, Blau, Nenad, additional, Goldmuntz, Elizabeth, additional, Schnog, John-John B., additional, Gerdes, Victor E. A., additional, Bonaventure, Jacky, additional, Nohr, Donatus, additional, Marinaki, Anthony M., additional, Arenas, Monica, additional, Groff IV, Robert F., additional, Huang, Jason H., additional, Cate, Hugo Ten, additional, Tefferi, Ayalew, additional, Tsai, Han-Mou, additional, Ibraheim, Mofid, additional, Ikomi, Amaj, additional, Olsson, Bob, additional, Wadenvik, Hans, additional, Ilcheff, Julian, additional, Bounameaux, Henri, additional, Righini, Marc, additional, Boos, Christopher J., additional, Lip, Gregory Y. H., additional, Ramot, Yuval, additional, Goldschmidt, Neta, additional, Nyska, Abraham, additional, Van Kuilenburg, André B. P., additional, Van Gennip*, Albert H., additional, Koch, Christian A., additional, Sarlis, Nicholas J., additional, Forrest, Douglas, additional, Kopp, Peter, additional, Sancak, Seda, additional, Eszlinger, Markus, additional, Paschke, Ralf, additional, Fioravanti, Antonella, additional, Mazzei, Maria Antonietta, additional, Coppola, Giuseppina, additional, Volterrani, Luca, additional, Zenner, Hans-Peter, additional, Zalaman, Ilse Maria, additional, Schumacher, Ulrike, additional, Autenrieth, Ingo B., additional, Wadhani, Nitin, additional, Red, Hari, additional, Azmoon, Shah, additional, Singh, Harpreet, additional, Singh, Bramah N., additional, Brown, David W., additional, Geva, Tal, additional, Guarneri, Claudio, additional, Borgia, Francesco, additional, Vaccaro, Mario, additional, Müller, Norbert, additional, Kohlhase, Jürgen, additional, Erhardt, Andreas, additional, Mboti, Freddy, additional, Yazdanbakhsh, Karina, additional, Sutton, Millicent, additional, Hillebrands, Jan-Luuk, additional, de Weger, Roel, additional, Rozing, Jan, additional, Leatherbury, Linda, additional, Lo, Cecilia, additional, Engel, Jutta, additional, Louis, Elan D., additional, Guarneri, Fabrizio, additional, Berneburg, Mark, additional, Schwarz, Thomas, additional, Krombach, Gabriele A., additional, Baldi, Alfonso, additional, Niwa, Koichiro, additional, Guran, Sefik, additional, Pugh, Trevor J., additional, Marra, Marco A., additional, Wolstenholme, John, additional, Hegde, Hardally R., additional, Richter, Joachim, additional, Yamagishi, Hiroyuki, additional, Fukuda, Keiichi, additional, Ledochowski, Maximilian, additional, Fuchs, Dietmar, additional, Agrawal, Pushpa, additional, Alam†, Md. Suhail, additional, Garg†, Saurabh K., additional, Wienecke, Ralf, additional, Capasso, Giovambattista, additional, Bernardi, Mauro, additional, Trevisani, Franco, additional, Nakamura, Kimitoshi, additional, Matsumoto, Shiro, additional, Mitsubuchi, Hiroshi, additional, and Endo, Fumio, additional

Published
2009
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50. Tyrosinemia Type III and Hawkinsinuria

Author

Raj, Satish R., primary, Chen, S. R. Wayne, additional, Sheldon, Robert S., additional, Shah, Arti N., additional, Kantharia, Bharat K., additional, Salzer, Ulrich, additional, Grimbacher, Bodo, additional, Leung, Alexander K. C., additional, Kamat, Deepak, additional, Kolovou, Genovefa D., additional, Anagnostopoulou, Katherine K., additional, Cokkinos, Dennis V., additional, Shinkai, Takahiro, additional, Quinlivan, Rosaline C. M., additional, Beynon, Robert, additional, Kolter, Thomas, additional, Schepers, Ute, additional, Sandhoff, Konrad, additional, Nicot, Christophe, additional, Kempf, Werner, additional, Dummer, Reinhard, additional, Burg, Günter, additional, Geisthoff, Urban W., additional, Bartholdi, Deborah, additional, Schinzel, Albert, additional, Bornstein, Stefan R., additional, Blau, Nenad, additional, Goldmuntz, Elizabeth, additional, Schnog, John-John B., additional, Gerdes, Victor E. A., additional, Bonaventure, Jacky, additional, Nohr, Donatus, additional, Marinaki, Anthony M., additional, Arenas, Monica, additional, Groff IV, Robert F., additional, Huang, Jason H., additional, Cate, Hugo Ten, additional, Tefferi, Ayalew, additional, Tsai, Han-Mou, additional, Ibraheim, Mofid, additional, Ikomi, Amaj, additional, Olsson, Bob, additional, Wadenvik, Hans, additional, Ilcheff, Julian, additional, Bounameaux, Henri, additional, Righini, Marc, additional, Boos, Christopher J., additional, Lip, Gregory Y. H., additional, Ramot, Yuval, additional, Goldschmidt, Neta, additional, Nyska, Abraham, additional, Van Kuilenburg, André B. P., additional, Van Gennip*, Albert H., additional, Koch, Christian A., additional, Sarlis, Nicholas J., additional, Forrest, Douglas, additional, Kopp, Peter, additional, Sancak, Seda, additional, Eszlinger, Markus, additional, Paschke, Ralf, additional, Fioravanti, Antonella, additional, Mazzei, Maria Antonietta, additional, Coppola, Giuseppina, additional, Volterrani, Luca, additional, Zenner, Hans-Peter, additional, Zalaman, Ilse Maria, additional, Schumacher, Ulrike, additional, Autenrieth, Ingo B., additional, Wadhani, Nitin, additional, Red, Hari, additional, Azmoon, Shah, additional, Singh, Harpreet, additional, Singh, Bramah N., additional, Brown, David W., additional, Geva, Tal, additional, Guarneri, Claudio, additional, Borgia, Francesco, additional, Vaccaro, Mario, additional, Müller, Norbert, additional, Kohlhase, Jürgen, additional, Erhardt, Andreas, additional, Mboti, Freddy, additional, Yazdanbakhsh, Karina, additional, Sutton, Millicent, additional, Hillebrands, Jan-Luuk, additional, de Weger, Roel, additional, Rozing, Jan, additional, Leatherbury, Linda, additional, Lo, Cecilia, additional, Engel, Jutta, additional, Louis, Elan D., additional, Guarneri, Fabrizio, additional, Berneburg, Mark, additional, Schwarz, Thomas, additional, Krombach, Gabriele A., additional, Baldi, Alfonso, additional, Niwa, Koichiro, additional, Guran, Sefik, additional, Pugh, Trevor J., additional, Marra, Marco A., additional, Wolstenholme, John, additional, Hegde, Hardally R., additional, Richter, Joachim, additional, Yamagishi, Hiroyuki, additional, Fukuda, Keiichi, additional, Ledochowski, Maximilian, additional, Fuchs, Dietmar, additional, Agrawal, Pushpa, additional, Alam†, Md. Suhail, additional, Garg†, Saurabh K., additional, Wienecke, Ralf, additional, Capasso, Giovambattista, additional, Bernardi, Mauro, additional, Trevisani, Franco, additional, Nakamura, Kimitoshi, additional, Matsumoto, Shiro, additional, Mitsubuchi, Hiroshi, additional, and Endo, Fumio, additional

Published
2009
Full Text
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