Article
Cardiac & Cardiovascular Systems
Matthew J. Wleklinski, Dmytro O. Kryshtal, Kyungsoo Kim, Shan S. Parikh, Daniel J. Blackwell, Isabelle Marty, V. Ramesh Iyer, Bjorn C. Knollmann
Summary: CASQ2-K180R causes CPVT2 through impairing dynamic buffering of Ca within the SR, which is different from other CASQ2-related forms of CPVT2.
CIRCULATION RESEARCH
(2022)
Article
Neurosciences
Xianwei Zhang, Charlotte E. R. Smith, Stefano Morotti, Andrew G. Edwards, Daisuke Sato, William E. Louch, Haibo Ni, Eleonora Grandi
Summary: This study investigates the independent and interactive effects of TATS and Ca2+-handling protein remodelling on Ca2+-handling abnormality driven membrane instabilities. The results show that the impact of protein remodelling on Ca2+-driven proarrhythmic behaviour varies depending on TATS density.
JOURNAL OF PHYSIOLOGY-LONDON
(2023)
Article
Biology
S. J. Richardson, C. G. Thekkedam, M. G. Casarotto, N. A. Beard, A. F. Dulhunty
Summary: Cardiac ryanodine receptors (RyR2) play a crucial role in releasing intracellular calcium essential for cardiac myocyte contraction. The regulation of ion channel opening by intracellular factors, including FK506 binding proteins FKBP12 and FKBP12.6, and their impact on RyR2 activity and cardiac contraction are still debated. This study demonstrates that FKBP12 activates RyR2 with high affinity and inhibits RyR2 with lower affinity, suggesting a model of negative cooperativity in FKBP12 binding. The dissociation of FKBP12/12.6 could dynamically affect RyR2 activity, indicating the significant role of FKBP12/12.6 in Ca2+ signaling and cardiac function.
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
(2023)
Article
Neurosciences
Peter Szentesi, Beatrix Dienes, Candice Kutchukian, Tamas Czirjak, Ana Buj-Bello, Vincent Jacquemond, Laszlo Csernoch
Summary: The study demonstrates that the alteration of the plasma membrane invagination network in MTM1 deficiency is sufficient to explain the dysfunctions of excitation-contraction coupling, providing an integrated quantitative framework for understanding the associated contraction failure.
JOURNAL OF PHYSIOLOGY-LONDON
(2023)
Article
Cardiac & Cardiovascular Systems
Adela Herraiz-Martinez, Carmen Tarifa, Veronica Jimenez-Sabado, Anna Llach, Hector Godoy-Marin, Hildegard Colino, Carme Nolla-Colomer, Sergi Casabella, Paloma Izquierdo-Castro, Ivan Benitez, Raul Benitez, Elena Rosello-Diez, Enrique Rodriguez-Font, Xavier Vinolas, Francisco Ciruela, Juan Cinca, Leif Hove-Madsen
Summary: Sex-dependent disturbances in calcium homeostasis in atrial fibrillation result in increased spontaneous sarcoplasmic reticulum calcium release-induced electrical activity in women, while men exhibit diminished L-type calcium current density. Females with AF have more calcium spark sites and longer sparks, leading to higher incidence of transient inward currents and afterdepolarizations.
CARDIOVASCULAR RESEARCH
(2022)
Article
Medicine, Research & Experimental
Maarten A. J. De Smet, Alessio Lissoni, Timur Nezlobinsky, Nan Wang, Eef Dries, Marta Perez-Hernandez, Xianming Lin, Matthew Amoni, Tim Vervliet, Katja Witschas, Eli Rothenberg, Geert Bultynck, Rainer Schulz, Alexander V. Panfilov, Mario Delmar, Karin R. Sipido, Luc Leybaert
Summary: Cx43 hemichannels are activated during diastolic Ca2+ release in ventricular cardiomyocytes, contributing to enhanced Ca2+ dynamics due to Ca2+ entry and coupling to release microdomains. Hemichannel opening also leads to delayed afterdepolarizations and triggered action potentials. Increased hemichannel activity is associated with electrical instability in failing human hearts compared to nonfailing donor hearts, suggesting a potentially novel mechanism of cardiac arrhythmogenesis in heart failure.
JOURNAL OF CLINICAL INVESTIGATION
(2021)
Article
Multidisciplinary Sciences
Carlo Manno, Eshwar Tammineni, Lourdes Figueroa, Isabelle Marty, Eduardo Rios
Summary: Triadin plays a key role in regulating calcium signaling and muscle function. Its knockout leads to alterations in calcium balance and changes in the expression of important proteins, such as calsequestrin. However, the muscle cells are able to compensate for these changes and maintain normal muscle function.
Article
Biochemistry & Molecular Biology
Bengt Svensson, Florentin R. Nitu, Robyn T. Rebbeck, Lindsey M. Mcgurran, Tetsuro Oda, David D. Thomas, Donald M. Bers, Razvan L. Cornea
Summary: Current studies have shown that Ca2+ leakage from cardiomyocyte sarcoplasmic reticulum through hyperactive resting cardiac ryanodine receptor channels (RyR2) has a pro-arrhythmic effect. An exogenous peptide (DPc10) binding promotes leaky RyR2 in cardiomyocytes and reports on the endogenous state. Conversely, binding of calmodulin (CaM) inhibits RyR2 leak and low CaM affinity is indicative of leaky RyR2. These findings have led to the development of a FRET biosensor for drug discovery targeting RyR2.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Takuya Kobayashi, Akihisa Tsutsumi, Nagomi Kurebayashi, Kei Saito, Masami Kodama, Takashi Sakurai, Masahide Kikkawa, Takashi Murayama, Haruo Ogawa
Summary: This study reveals the gating mechanism of RyR2 and how it is altered by pathogenic mutations through high-resolution structures and functional analysis.
NATURE COMMUNICATIONS
(2022)
Review
Pharmacology & Pharmacy
Mohit M. Hulsurkar, Satadru K. Lahiri, Jason Karch, Meng C. Wang, Xander H. T. Wehrens
Summary: This article discusses the abnormal calcium signaling between organelles and its role in heart diseases. It examines various calcium channels and transporters involved in inter-organellar calcium signaling and highlights the dysregulation of calcium homeostasis in cardiac diseases. Furthermore, it suggests that targeting these calcium channels may represent a promising therapeutic strategy for heart diseases.
EXPERT OPINION ON THERAPEUTIC TARGETS
(2022)
Review
Pharmacology & Pharmacy
Yuxin Du, Laurie J. Demillard, Jun Ren
Summary: This article summarizes the normal regulation of SR Ca2+ in cardiomyocytes, the mechanisms of how Ca2+ triggers arrhythmias, the involvement of SR gene mutations in inherited arrhythmias, and the possible arrhythmogenic effects of these mutations.
BIOCHEMICAL PHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
Fujian Lu, Qing Ma, Wenjun Xie, Carter L. Liou, Donghui Zhang, Mason E. Sweat, Blake D. Jardin, Francisco J. Naya, Yuxuan Guo, Heping Cheng, William T. Pu
Summary: This study uncovers the role of CMYA5 in organizing and regulating the subcellular structures in cardiomyocytes, highlighting its importance in cardiac development, function, and tolerance to pressure overload.
NATURE COMMUNICATIONS
(2022)
Article
Cell Biology
Matteo Serano, Laura Pietrangelo, Cecilia Paolini, Flavia A. Guarnier, Feliciano Protasi
Summary: Calsequestrin 1 (CASQ1) and Ryanodine receptor 1 (RYR1) play important roles in excitation-contraction coupling. CASQ1-null and Y522S mice have increased food consumption, higher core temperature at rest, and increased oxygen consumption. Y522S mice are more susceptible to hypermetabolic crises compared to CASQ1-null mice.
Article
Cell Biology
Evan P. Campbell, Ahmed A. Abushawish, Lauren A. Valdez, Miriam K. Bell, Melita Haryono, Padmini Rangamani, Brenda L. Bloodgood
Summary: The study visualizes the dynamics of endoplasmic reticulum (ER) membrane potential and explores if ER ion channels can trigger membrane potential fluctuations that spread beyond their origin. They find that in neurons, stimulation of ER ryanodine receptors generates depolarizations that are restricted from impacting nearby membranes. This suggests that segments of ER can generate large depolarizations but they are contained within their site of activation.
Article
Pharmacology & Pharmacy
Giampaolo Morciano, Alessandro Rimessi, Simone Patergnani, Veronica A. M. Vitto, Alberto Danese, Asrat Kahsay, Laura Palumbo, Massimo Bonora, Mariusz R. Wieckowski, Carlotta Giorgi, Paolo Pinton
Summary: Intracellular calcium signaling is a universal language shared by various biological entities inside cells, regulating physiological functions like muscle contraction through calcium channels, pumps, and exchangers. Abnormal calcium homeostasis can lead to heart diseases, but can be corrected through chemical, peptide-based, and pharmacological modulators.
PHARMACOLOGICAL RESEARCH
(2022)
Article
Cell Biology
Claudio F. Perez, Jose M. Eltit, Jose R. Lopez, Dora Bodnar, Angela F. Dulhunty, Shouvik Aditya, Marco G. Casarotto
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2018)
Article
Genetics & Heredity
Fabien Vanden Abeele, Sabine Lotteau, Sylvie Ducreux, Charlotte Dubois, Nicole Monnier, Amy Hanna, Dimitra Gkika, Caroline Romestaing, Lucile Noyer, Matthieu Flourakis, Nolwenn Tessier, Ribal Al-Mawla, Christophe Chouabe, Etienne Lefai, Joel Lunardi, Susan Hamilton, Julien Faure, Fabien Van Coppenolle, Natalia Prevarskaya
GENETICS IN MEDICINE
(2019)
Article
Biochemistry & Molecular Biology
Amanda Denniss, Angela F. Dulhunty, Nicole A. Beard
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
(2018)
Article
Pharmacology & Pharmacy
A. D. Chakraborty, L. A. Gonano, M. L. Munro, L. J. Smith, C. Thekkedam, V. Staudacher, A. B. Gamble, N. Macquaide, A. F. Dulhunty, P. P. Jones
BRITISH JOURNAL OF PHARMACOLOGY
(2019)
Article
Cell Biology
Samantha C. Salvage, Esther M. Gallant, Nicole A. Beard, Shiraz Ahmad, Haseeb Valli, James A. Fraser, Christopher L. -H. Huang, Angela F. Dulhunty
JOURNAL OF CELL SCIENCE
(2019)
Article
Multidisciplinary Sciences
Hui J. Wang, Chang Seok Lee, Rachel Sue Zhen Yee, Linda Groom, Inbar Friedman, Lyle Babcock, Dimitra K. Georgiou, Jin Hong, Amy D. Hanna, Joseph Recio, Jong Min Choi, Ting Chang, Nadia H. Agha, Jonathan Romero, Poonam Sarkar, Nicol Voermans, M. Waleed Gaber, Sung Yun Jung, Matthew L. Baker, Robia G. Pautler, Robert T. Dirksen, Sheila Riazi, Susan L. Hamilton
NATURE COMMUNICATIONS
(2020)
Article
Anesthesiology
Barbara Bojko, Tijana Vasiljevic, Ezel Boyaci, Anna Roszkowska, Natalia Kraeva, Carlos A. Ibarra Moreno, Annabel Koivu, Marcin Wasowicz, Amy Hanna, Susan Hamilton, Sheila Riazi, Janusz Pawliszyn
Summary: The study found significant fold-change differences in metabolites from various pathways between MH-susceptible and control groups, indicating a shift from carbohydrate to lipid utilization for energy production in MH-susceptible individuals. This shift may lead to inefficiency of beta-oxidation, increased muscle protein turnover, oxidative stress, and/or elevated lysophosphatidylcholine levels.
CANADIAN JOURNAL OF ANESTHESIA-JOURNAL CANADIEN D ANESTHESIE
(2021)
Article
Cell Biology
Lyle W. Babcock, Amy D. Hanna, Nadia H. Agha, Susan L. Hamilton
Article
Biochemistry & Molecular Biology
Amy D. Hanna, Chang Seok Lee, Lyle Babcock, Hui Wang, Joseph Recio, Susan L. Hamilton
Summary: The study indicates that the myopathy associated with the D244G mutation in CASQ1 is driven by CASQ1 mislocalization and aggregation, reduced SR calcium release, leading to ER stress, increased protein aggregation, and other pathological changes in muscle cells.
Article
Physiology
Samantha C. Salvage, Christopher L. -H. Huang, James A. Fraser, Angela F. Dulhunty
Summary: Flecainide, an antiarrhythmic drug, can reduce calcium ion release in the heart through multiple molecular mechanisms. It plays an important role in the treatment of catecholaminergic polymorphic ventricular tachycardia (CPVT).
JOURNAL OF GENERAL PHYSIOLOGY
(2022)
Review
Biology
Samantha C. C. Salvage, Angela F. F. Dulhunty, Kamalan Jeevaratnam, Antony P. P. Jackson, Christopher L. -H. Huang
Summary: Skeletal and cardiac muscle excitation-contraction coupling involves the interaction between Na(v)1.4/Na(v)1.5 and Cav1.1/Cav1.2 channels, as well as RyR1/RyR2 receptors, mediated by SR Ca2+ release. Studies have shown the potential feedback actions of SR Ca2+ release on Na(v)1.4/Na(v)1.5 function. Experimental observations have revealed the effects of RyR inhibitors and activators on Na+ currents in muscle fibers and cardiomyocytes. The modulation of Ca2+ transients and AP conduction has implications for arrhythmogenicity.
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
(2023)
Article
Biology
S. J. Richardson, C. G. Thekkedam, M. G. Casarotto, N. A. Beard, A. F. Dulhunty
Summary: Cardiac ryanodine receptors (RyR2) play a crucial role in releasing intracellular calcium essential for cardiac myocyte contraction. The regulation of ion channel opening by intracellular factors, including FK506 binding proteins FKBP12 and FKBP12.6, and their impact on RyR2 activity and cardiac contraction are still debated. This study demonstrates that FKBP12 activates RyR2 with high affinity and inhibits RyR2 with lower affinity, suggesting a model of negative cooperativity in FKBP12 binding. The dissociation of FKBP12/12.6 could dynamically affect RyR2 activity, indicating the significant role of FKBP12/12.6 in Ca2+ signaling and cardiac function.
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
(2023)
Article
Biology
Chang Seok Lee, Sung Yun Jung, Rachel Sue Zhen Yee, Nadia H. Agha, Jin Hong, Ting Chang, Lyle W. Babcock, Jorie D. Fleischman, Benjamin Clayton, Amy D. Hanna, Christopher S. Ward, Denise Lanza, Ayrea E. Hurley, Pumin Zhang, Xander H. T. Wehrens, William R. Lagor, George G. Rodney, Susan L. Hamilton
Summary: Speg alpha maintains cardiac function in hearts with Speg beta deficiency, suggesting functional redundancy. This study identifies Esd, Cmya5, and Fsd2 as important components in cardiac and skeletal muscle and provides potential new therapeutic targets for centronuclear myopathy.
COMMUNICATIONS BIOLOGY
(2023)
Review
Biophysics
Angela F. Dulhunty
Summary: The discovery of gating currents and asymmetric charge movement in the early 1970s has greatly advanced our understanding of the biophysical basis of voltage-dependent events in nerve and muscle function. The detection of these currents and charge movement has been crucial in unraveling the molecular and intra-molecular processes underlying action potentials and excitation-contraction coupling in excitable tissues.
BIOPHYSICAL REVIEWS
(2023)
Review
Pharmacology & Pharmacy
Samantha C. Salvage, Karthik H. Chandrasekharan, Kamalan Jeevaratnam, Angela F. Dulhunty, Andrew J. Thompson, Antony P. Jackson, Christopher L-H Huang
BRITISH JOURNAL OF PHARMACOLOGY
(2018)
Article
Cell Biology
Dominic Tscherrig, Rajesh Bhardwaj, Daniel Biner, Jan Dernic, Daniela Ross-Kaschitza, Christine Peinelt, Matthias A. Hediger, Martin Lochner
Summary: Changes in Ca2+ levels regulate many physiological functions, and the endoplasmic reticulum is the major Ca2+ store in cells. Store-operated calcium entry (SOCE) is a refilling process that involves protein-protein interactions between Ca2+ sensing STIM in the ER and Orai proteins in the plasma membrane, forming selective Ca2+ channels. Abnormal SOCE is associated with diseases and cancers, making STIM and Orai important therapeutic targets. Novel GSK-7975A-based molecular probes have been developed for studying SOCE in different cells and settings.
Article
Cell Biology
Nicola Fameli, Cornelis van Breemen, Klaus Groschner
Summary: The study provides evidence for the importance of junctional membrane architecture in cellular function. Through modeling and prediction, it is shown that nano-scale membrane spacing plays a crucial role in junctional ER Ca2+ refilling and signaling efficiency. Additionally, interactions between Ca2+ and the phospholipid membrane surface are suggested to support interfacial Ca2+ transport and receptor targeting. This research introduces a new concept in pathophysiology.
Article
Cell Biology
Satomi Ohtsuka, Yumi Miyai, Hiroyuki Mima, Masaki Magari, Yoichi Chiba, Futoshi Suizu, Hiroyuki Sakagami, Masaki Ueno, Hiroshi Tokumitsu
Summary: This study characterized the splice variants of mouse CaMKKI3/2 and found that CaMKKI3-3 and I3-3x were functionally active and likely to be bona fide CaMKIV kinases involved in the regulation of spermiogenesis.