Article
Cell Biology
Steven E. E. Cala, Nicholas J. J. Carruthers, Paul M. M. Stemmer, Zhenhui Chen, Xuequn Chen
Summary: The importance of sarcoplasmic reticulum (SR) Ca2+-handling in heart has been extensively studied, while the understanding of other endoplasmic reticulum (ER) functions in the heart is limited. This research aimed to analyze cardiac microsomes to gain a better understanding of cardiac SR and ER functions. The results showed that different proteins exhibited varying levels of enrichment in SR fractions compared to the crude membrane preparation, indicating functional sets of proteins localized to the same areas of the ER/SR membrane. This study suggests that the combined activities of Ca2+ uptake by SERCA and Ca2+ leak by RyR contribute to the evaluation of multiple functional ER/SR subdomains.
MOLECULAR AND CELLULAR BIOCHEMISTRY
(2023)
Article
Cardiac & Cardiovascular Systems
Ruben Lopez, Radoslav Janicek, Miguel Fernandez-Tenorio, Marianne Courtehoux, Lluis Matas, Pascale Gerbaud, Ana M. Gomez, Marcel Egger, Ernst Niggli
Summary: This study found that beta-adrenergic receptor (β-AR) activation and stimulation of SR Ca2+ pump (SERCA) can lead to higher frequencies of Ca2+ waves in cardiomyocytes with the RyR2R420Q+/- mutation. The phosphorylation of RyR2s and the resulting SR Ca2+ leak may play a role in this phenomenon.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2022)
Article
Neurosciences
Daisuke Sato, Hitoshi Uchinoumi, Donald M. Bers
Summary: Increasing SERCA activity has a dual effect on the propensity of arrhythmogenic Ca waves, promoting their generation at lower levels but potentially aborting them at higher levels. Factors influencing Ca wave propagation include diffusive coupling between Ca sparks, Ca buffers, intra-SR Ca diffusion, and distance between CRUs.
JOURNAL OF PHYSIOLOGY-LONDON
(2021)
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
Biochemistry & Molecular Biology
Ayako Takeuchi, Satoshi Matsuoka
Summary: In this study, the spatial and functional coupling between mitochondrial Na+-Ca2+ exchanger (NCLX) and sarcoplasmic reticulum Ca2+ pump SERCA in cardiomyocytes was investigated. The results demonstrated a close interaction between NCLX and SERCA, indicating their important role in modulating cellular functions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Physiology
Adan Dagnino-Acosta, Agustin Guerrero-Hernandez
Summary: PKC inhibitors stimulate Ca2+ release from internal stores by increasing SR Ca2+ leak mediated by translocon activation. This increased leak does not deplete the Ca2+ store, but rather compensates by increasing SERCA pump activity, leading to a new steady-state level. This change also results in increased activity of high conductance, Ca2+-sensitive potassium channels.
FRONTIERS IN PHYSIOLOGY
(2022)
Review
Cardiac & Cardiovascular Systems
Changwon Kho
Summary: Impaired myocardial Ca2+ cycling is a crucial factor in the development of heart failure, leading to changes in contractile function and structural remodeling of the heart. The regulation of sarcoplasmic reticulum Ca2+ storage and release in cardiomyocytes relies heavily on Ca2+ handling proteins like SERCA2a pump. However, reduced expression and activity of SERCA2a are key features of heart failure, resulting in a growing interest in therapeutic approaches targeting SERCA2a. This review provides an overview of the regulatory mechanisms of the SERCA2a pump and explores potential strategies for SERCA2a-targeted therapy in both preclinical and clinical studies.
FRONTIERS IN CARDIOVASCULAR MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Jun Nakamura, Yuusuke Maruyama, Genichi Tajima, Satoshi Hayakawa, Makiko Suwa, Chikara Sato
Summary: The crystallization of Ca2+-ATPase molecules in sarcoplasmic reticulum vesicles is dependent on the concentration of Ca2+ ions, with ATP stabilizing the crystals. By using negative stain electron microscopy, it was observed that the length of SR vesicles is dependent on the [Ca2+] in the presence of ATP, with elongation occurring at <= 1.4 μM Ca2+ and contraction at >= 18 μM Ca2+. The crystallization of ATPase at high Ca2+ concentrations suggests a role in modulating the physical properties of SR architecture and muscle contraction.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
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
Cell Biology
Daiki Watanabe, Masanobu Wada
Summary: The study found that the increased Ca2+ leakage after muscle contractions is mainly caused by the orthograde signal of DHPRs to RyRs. By experimentally measuring SR Ca2+ leakage in the skinned fibers under continuously depolarized conditions, it was shown that the level of Ca2+ leakage reached a similar level to that in stimulated fibers.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2021)
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
Cardiac & Cardiovascular Systems
Jinhong Wei, Wenting Guo, Ruiwu Wang, John Paul Estillore, Darrell Belke, Yong-Xiang Chen, Alexander Vallmitjana, Raul Benitez, Leif Hove-Madsen, S. R. Wayne Chen
Summary: The physiological significance of PKA phosphorylation of RyR2 in the heart is still poorly understood. Recent structural studies have shown that the PKA phosphorylation site S2030 in RyR2 is located within a pathway that is important for the termination of Ca2+ release. We investigated the impact of S2030 mutations on Ca2+ release termination in cells and generated a mouse model to study the role of S2030 in a physiological setting.
CIRCULATION RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Michael Arzt, Marzena A. Drzymalski, Sarah Ripfel, Sebastian Meindl, Alexander Biedermann, Melanie Durczok, Karoline Keller, Julian Mustroph, Sylvia Katz, Maria Tafelmeier, Simon Lebek, Bernhard Floerchinger, Daniele Camboni, Sigrid Wittmann, Johannes Backs, Christof Schmid, Lars S. Maier, Stefan Wagner
Summary: Patients with sleep-disordered breathing (SDB) have increased oxidized and activated CaMKII levels and CaMKII-dependent Ca spark frequency in the atrial myocardium, independent of major clinical confounders.
Article
Cardiac & Cardiovascular Systems
Jinhong Wei, Jinjing Yao, Darrell Belke, Wenting Guo, Xiaowei Zhong, Bo Sun, Ruiwu Wang, John Paul Estillore, Alexander Vallmitjana, Raul Benitez, Leif Hove-Madsen, Enrique Alvarez-Lacalle, Blas Echebarria, S. R. Wayne Chen
Summary: The study demonstrates that CaM-mediated inactivation of RyR2 plays a crucial role in cardiac alternans, highlighting the potential of CaM-dependent regulation of RyR2 as an important therapeutic target for arrhythmias.
CIRCULATION RESEARCH
(2021)
Article
Pharmacology & Pharmacy
Weimin Yu, Gang Xu, Hui Chen, Li Xiao, Gang Liu, Pingping Hu, Siqi Li, Vivi Kasim, Chunyu Zeng, Xiaoyong Tong
Summary: Pulmonary hypertension (PH) is a life-threatening disease characterized by pulmonary vascular remodeling and hyperproliferation of pulmonary artery smooth muscle cells (PASMCs). This study identifies the impact of C674 oxidative inactivation on pulmonary vascular remodeling and PH development, highlighting the importance of C674 in maintaining pulmonary vascular homeostasis by restricting PASMC proliferation. The IRE1 alpha/XBP1s pathway and SERCA2 may serve as potential targets for PH therapy.
ACTA PHARMACEUTICA SINICA B
(2022)