Dantrolene rescues arrhythmogenic RYR2 defect in a patient‐specific stem cell model of catecholaminergic polymorphic ventricular tachycardia
Open accessAbstract
Coordinated release of calcium (Ca(2+) ) from the sarcoplasmic reticulum (SR) through cardiac ryanodine receptor (RYR2) channels is essential for cardiomyocyte function. In catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited disease characterized by stress-induced ventricular arrhythmias in young patients with structurally normal hearts, autosomal dominant mutations in RYR2 or recessive mutations in calsequestrin lead to aberrant diastolic Ca(2+) release from the SR causing arrhythmogenic delayed after depolarizations (DADs). Here, we report the generation of induced pluripotent stem cells (iPSCs) from a CPVT patient carrying a novel RYR2 S406L mutation. In patient iPSC-derived cardiomyocytes, catecholaminergic stress led to elevated diastolic Ca(2+) concentrations, a reduced SR Ca(2+) content and an increased susceptibility to DADs and arrhythmia as compared to control myocytes. This was due to increased frequency and duration of elementary Ca(2+) release events (Ca(2+) sparks). Dantrolene, a drug effective on malignant hyperthermia, restored normal Ca(2+) spark properties and rescued the arrhythmogenic phenotype. This suggests defective inter-domain interactions within the RYR2 channel as the pathomechanism of the S406L mutation. Our work provides a new in vitro model to study the pathogenesis of human cardiac arrhythmias and develop novel therapies for CPVT.
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Patient-specific genotype can significantly affect disease onset and progression and influence drug responses.
“It is known that patient-specific genotype can significantly affect disease onset and progression, as well as influence drug responses [211,214,410].”
From Cardiovascular disease models: A game changing paradigm in drug discovery and screening (2019) · cites this paper as [410]
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Cites
A new generation of Ca2+ indicators with greatly improved fluorescence properties.
Grynkiewicz, G., Poenie, M., & Tsien, R. Y. (1985) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)83641-4 · Cited by 21,722 · see citing works
Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors
Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007) · Cell · doi:10.1016/j.cell.2007.11.019 · Cited by 20,221 · see citing works
PKA Phosphorylation Dissociates FKBP12.6 from the Calcium Release Channel (Ryanodine Receptor)
Marx, S. O., Reiken, S. R., Hisamatsu, Y., Jayaraman, T., Burkhoff, D., Rosemblit, N., & Marks, A. R. (2000) · Cell · doi:10.1016/s0092-8674(00)80847-8 · Cited by 1,981 · see citing works
Calcium Sparks: Elementary Events Underlying Excitation-Contraction Coupling in Heart Muscle
Cheng, H., Lederer, W. J., & Cannell, M. B. (1993) · Science · doi:10.1126/science.8235594 · Cited by 1,941 · see citing works
Priori, S. G., Napolitano, C., Tiso, N., Memmi, M., Vignati, G., Bloise, R., Sorrentino, V., & Danieli, G. A. (2001) · Circulation · doi:10.1161/01.cir.103.2.196 · Cited by 1,378 · see citing works
Patient-Specific Induced Pluripotent Stem-Cell Models for Long-QT Syndrome
Moretti, A., Bellin, M., Welling, A., Jung, C. B., Lam, J. T., Bott-Flügel, L., Dorn, T., Goedel, A., Höhnke, C., Hofmann, F., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0908679 · Cited by 1,251 · see citing works
Self-citationRyanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium ReleasePreprint
Lanner, J. T., Georgiou, D. K., Joshi, A., & Hamilton, S. L. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a003996 · Cited by 820 · see citing works
Wehrens, X. H. T., Lehnart, S. E., Huang, F., Vest, J. A., Reiken, S. R., Mohler, P. J., Sun, J., Guatimosim, S., Song, L., Rosemblit, N., et al. (2003) · Cell · doi:10.1016/s0092-8674(03)00434-3 · Cited by 760 · see citing works
Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome
Carvajal-Vergara, X., Sevilla, A., D’Souza, S. L., Ang, Y.-S., Schaniel, C., Lee, D.-F., Yang, L., Kaplan, A. D., Adler, E. D., Rozov, R., et al. (2010) · Nature · doi:10.1038/nature09005 · Cited by 690 · see citing works
Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome
Yazawa, M., Hsueh, B., Jia, X., Pasca, A. M., Bernstein, J. A., Hallmayer, J., & Dolmetsch, R. E. (2011) · Nature · doi:10.1038/nature09855 · Cited by 677 · see citing works
Dantrolene – A review of its pharmacology, therapeutic use and new developments
Krause, T., Gerbershagen, M. U., Fiege, M., Weißhorn, R., & Wappler, F. (2004) · Anaesthesia · doi:10.1111/j.1365-2044.2004.03658.x · Cited by 578 · see citing works
Inherited Dysfunction of Sarcoplasmic Reticulum Ca 2+ Handling and Arrhythmogenesis
Priori, S. G., & Chen, S. R. W. (2011) · Circulation Research · doi:10.1161/circresaha.110.226845 · Cited by 442 · see citing works
Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice
Lehnart, S. E., Mongillo, M., Bellinger, A. M., Lindegger, N., Chen, B.-X., HSUEH, W. H., Reiken, S. R., Wronska, A., Drew, L., Ward, C. W., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci35346 · Cited by 413 · see citing works
Postma, A. V., Denjoy, I., Hoorntje, T. M., Lupoglazoff, J., Costa, A. D., Sébillon, P., Mannens, M. M. A. M., Wilde, A. A. M., & Guicheney, P. (2002) · Circulation Research · doi:10.1161/01.res.0000038886.18992.6b · Cited by 409 · see citing works
Jiang, D., Wang, R., Xiao, B., Kong, H., Hunt, D. J., Choi, P. M. C., Zhang, L., & Chen, S. R. W. (2005) · Circulation Research · doi:10.1161/01.res.0000192146.85173.4b · Cited by 359 · see citing works
Arrhythmogenesis in Catecholaminergic Polymorphic Ventricular Tachycardia
Liu, N., Colombi, B., Memmi, M., et al. (2006) · Circulation Research · doi:10.1161/01.res.0000235869.50747.e1 · Cited by 314 · see citing works
Sarcoplasmic Reticulum Ca 2+ Release Causes Myocyte Depolarization
Schlotthauer, K., & Bers, D. M. (2000) · Circulation Research · doi:10.1161/01.res.87.9.774 · Cited by 310 · see citing works
Macromolecular complexes regulating cardiac ryanodine receptor function
Bers, D. M. (2004) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2004.05.026 · Cited by 308 · see citing works
George, C. H., Higgs, G. V., & Lai, F. A. (2003) · Circulation Research · doi:10.1161/01.res.0000091335.07574.86 · Cited by 256 · see citing works
Györke, S., & Terentyev, D. A. (2007) · Cardiovascular Research · doi:10.1093/cvr/cvm038 · Cited by 252 · see citing works
The amino-terminal disease hotspot of ryanodine receptors forms a cytoplasmic vestibule
Tung, C., Lobo, P. A., Kimlicka, L., & Petegem, F. V. (2010) · Nature · doi:10.1038/nature09471 · Cited by 218 · see citing works
Kobayashi, S., Yano, M., Suetomi, T., et al. (2009) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2009.01.065 · Cited by 192 · see citing works
Uchinoumi, H., Yano, M., Suetomi, T., et al. (2010) · Circulation Research · doi:10.1161/circresaha.109.209312 · Cited by 168 · see citing works
George, C. H., Jundi, H., Thomas, N. L., Fry, D. L., & Lai, F. A. (2006) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2006.08.115 · Cited by 163 · see citing works
Guo, T., Cornea, R. L., Huke, S., et al. (2010) · Circulation Research · doi:10.1161/circresaha.110.219816 · Cited by 160 · see citing works
Identification of a Dantrolene-binding Sequence on the Skeletal Muscle Ryanodine Receptor
Paul-Pletzer, K., Yamamoto, T., Bhat, M. B., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205487200 · Cited by 155 · see citing works
Dantrolene Stabilizes Domain Interactions within the Ryanodine Receptor
Kobayashi, S., Bannister, M. L., Gangopadhyay, J. P., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408375200 · Cited by 129 · see citing works
Postulated Role of Interdomain Interaction within the Ryanodine Receptor in Ca2+ Channel Regulation
Yamamoto, T., El-Hayek, R., & Ikemoto, N. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.16.11618 · Cited by 127 · see citing works
Kobayashi, S., Yano, M., Uchinoumi, H., et al. (2010) · Circulation Journal · doi:10.1253/circj.cj-10-0680 · Cited by 125 · see citing works
Xiao, J., Tian, X., Jones, P. P., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m707423200 · Cited by 113 · see citing works
Moretti, A., Bellin, M., Jung, C. B., Thies, T., Takashima, Y., Bernshausen, A., Schiemann, M., Fischer, S., Moosmang, S., Smith, A. G., et al. (2009) · The FASEB Journal · doi:10.1096/fj.09-139477 · Cited by 113 · see citing works
Self-citationInvestigating monogenic and complex diseases with pluripotent stem cells
Zhu, H., Lensch, M. W., Cahan, P., & Daley, G. (2011) · Nature reviews genetics · doi:10.1038/nrg2951 · Cited by 112 · see citing works
Kaufman, E. S. (2009) · Heart Rhythm · doi:10.1016/j.hrthm.2009.02.009 · Cited by 104 · see citing works
Gupta, M. K., Illich, D. J., Gaarz, A., Matzkies, M., Nguemo, F., Pfannkuche, K., Liang, H., Claßen, S., Reppel, M., Schultze, J. L., et al. (2010) · BMC Developmental Biology · doi:10.1186/1471-213x-10-98 · Cited by 91 · see citing works
Tateishi, H., Yano, M., Mochizuki, M., et al. (2008) · Cardiovascular Research · doi:10.1093/cvr/cvn303 · Cited by 91 · see citing works
Berridge, M. J. (2003) · Biochemical Society Transactions · doi:10.1042/bst0310930 · Cited by 76 · see citing works
Probing a putative dantrolene-binding site on the cardiac ryanodine receptor
Paul-Pletzer, K., Yamamoto, T., Ikemoto, N., et al. (2005) · Biochemical Journal · doi:10.1042/bj20041336 · Cited by 73 · see citing works
Postulated Role of Inter-domain Interaction within the Ryanodine Receptor in Ca2+ Channel Regulation
Ikemoto, N. (2000) · Trends in Cardiovascular Medicine · doi:10.1016/s1050-1738(01)00067-6 · Cited by 72 · see citing works
Liu, N., Rizzi, N., Boveri, L., & Priori, S. G. (2008) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2008.10.012 · Cited by 68 · see citing works
From the Ryanodine Receptor to Cardiac Arrhythmias
Eisner, D. A., Kashimura, T., Venetucci, L. A., & Trafford, A. W. (2009) · Circulation Journal · doi:10.1253/circj.cj-09-0478 · Cited by 67 · see citing works
Wang, R., Zhong, X., Meng, X. M., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.194316 · Cited by 56 · see citing works
Reversing Advanced Heart Failure by Targeting Ca2+Cycling
Kaye, D. M., Hoshijima, M., & Chien, K. R. (2008) · Annual Review of Medicine · doi:10.1146/annurev.med.59.052407.103237 · Cited by 45 · see citing works
Liu, Z., Wang, R., Tian, X., et al. (2010) · Journal of Cell Science · doi:10.1242/jcs.064071 · Cited by 44 · see citing works
Ryanodine receptor mutations in arrhythmia: The continuing mystery of channel dysfunction
Thomas, N. L., Maxwell, C. E., Mukherjee, S., & Williams, A. J. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.01.057 · Cited by 25 · see citing works
Exercise-Induced Ventricular Arrhythmias in Patients with No Structural Cardiac Disease
Scheinman, M. M., & Lam, J. T. (2006) · Annual Review of Medicine · doi:10.1146/annurev.med.57.081704.090151 · Cited by 10 · see citing works
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Benam, K. H., Dauth, S., Hassell, B., Herland, A., Jain, A., Jang, K.-J., Karalis, K., Kim, H. J., MacQueen, L., Mahmoodian, R., et al. (2015) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-012414-040418 · Cited by 554 · see citing works
Karakikes, I., Ameen, M., Termglinchan, V., & Wu, J. C. (2015) · Circulation Research · doi:10.1161/circresaha.117.305365 · Cited by 478 · see citing works
Denning, C., Borgdorff, V., Crutchley, J., Firth, K. S. A., George, V., Kalra, S., Kondrashov, A., Hoang, M. D., Mosqueira, D., Patel, A., et al. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.10.014 · Cited by 293 · see citing works
Tissue Engineering Approaches in the Design of Healthy and Pathological In Vitro Tissue Models
Caddeo, S., Boffito, M., & Sartori, S. (2017) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2017.00040 · Cited by 285 · see citing works
Cardiovascular disease models: A game changing paradigm in drug discovery and screening
Savoji, H., Mohammadi, M. H., Rafatian, N., Toroghi, M. K., Wang, E. Y., Zhao, Y., Korolj, A., Ahadian, S., & Radisic, M. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2018.09.036 · Cited by 223 · see citing works
Induced pluripotent stem cells: at the heart of cardiovascular precision medicine
Chen, I. Y., Matsa, E., & Wu, J. C. (2016) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2016.36 · Cited by 191 · see citing works
Park, S.-J., Zhang, D., Qi, Y., Li, Y., Lee, K. Y., Bezzerides, V. J., Yang, P., Xia, S., Kim, S. L., Liu, X., et al. (2019) · Circulation · doi:10.1161/circulationaha.119.039711 · Cited by 140 · see citing works
Matsa, E., Ahrens, J. H., & Wu, J. C. (2016) · Physiological Reviews · doi:10.1152/physrev.00036.2015 · Cited by 105 · see citing works
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Campostrini, G., Windt, L. M., van Meer, B. J., Bellin, M., & Mummery, C. L. (2021) · Circulation Research · doi:10.1161/circresaha.121.318183 · Cited by 96 · see citing works
Self-citationParrotta, E. I., Lucchino, V., Scaramuzzino, L., Scalise, S., & Cuda, G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21124354 · Cited by 88 · see citing works
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Li, S., Chen, G., & Li, R. A. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2013.256495 · Cited by 76 · see citing works
Devalla, H. D., & Passier, R. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aah5457 · Cited by 75 · see citing works
Human heart disease: lessons from human pluripotent stem cell-derived cardiomyocytes
Giacomelli, E., Mummery, C. L., & Bellin, M. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2546-5 · Cited by 60 · see citing works
Self-citation
- Authors
- Jung, C. B., Moretti, A., Mederos y Schnitzler, M., Iop, L., Storch, U., Bellin, M., Dorn, T., Ruppenthal, S., Pfeiffer, S., Goedel, A., Dirschinger, R. J., Seyfarth, M., Lam, J. T., Sinnecker, D., Gudermann, T., Lipp, P., & Laugwitz, K.
- Affiliations
- TUM Klinikum (DE)
- Walther-Straub-Institut für Pharmakologie und Toxikologie (DE)
- Universitätsklinikum des Saarlandes (DE)
- Witten/Herdecke University (DE)
- Corresponding author
- Gudermann, Thomas
- Lipp, Peter
- Laugwitz, Karl‐Ludwig
- ORCID
- Venue
- EMBO Molecular Medicine
- Published
- 2012-01-25
- Volume
- 4
- Issue
- 3
- Pages
- 180-191
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC3376852
- OpenAlex
- W2165179483
- Cited by
- 327
- References
- 45
- Citations by year
- 2026: 1 · 2025: 9 · 2024: 9 · 2023: 10 · 2022: 4 · 2021: 30 · 2020: 17 · 2019: 17 · 2018: 32 · 2017: 32 · 2016: 37 · 2015: 41 · 2014: 27 · 2013: 36 · 2012: 25
- FWCI
- 19.29
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by)
- Funders
- European Research Council (Marie Curie Excellence Team (MEXT‐23208; ERC 261053–CHD‐iPS)
- German Ministry for Education and Research (01 GN 0826)
- National Research Fund, Luxembourg
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
- Keywords
- catecholaminergic polymorphic ventricular tachycardia, RyR2, dantrolene, iPSC-derived cardiomyocytes, calcium sparks, diastolic calcium release, sarcoplasmic reticulum calcium, delayed afterdepolarizations, cardiac arrhythmias, malignant hyperthermia
- MeSH terms
- Polymorphic Catecholaminergic Ventricular Tachycardia, Adult, Calcium, Cells, Cultured, Dantrolene, Female, Humans, Models, Biological, Sarcoplasmic Reticulum, Ion Transport, Tachycardia, Ventricular, Ryanodine Receptor Calcium Release Channel, Myocytes, Cardiac, Induced Pluripotent Stem Cells
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