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https://www.readbyqxmd.com/read/28740084/ryanodine-receptors-are-part-of-the-myospryn-complex-in-cardiac-muscle
#1
Matthew A Benson, Caroline L Tinsley, Adrian J Waite, Francesca A Carlisle, Steve M M Sweet, Elisabeth Ehler, Christopher H George, F Anthony Lai, Enca Martin-Rendon, Derek J Blake
The Cardiomyopathy-associated gene 5 (Cmya5) encodes myospryn, a large tripartite motif (TRIM)-related protein found predominantly in cardiac and skeletal muscle. Cmya5 is an expression biomarker for a number of diseases affecting striated muscle and may also be a schizophrenia risk gene. To further understand the function of myospryn in striated muscle, we searched for additional myospryn paralogs. Here we identify a novel muscle-expressed TRIM-related protein minispryn, encoded by Fsd2, that has extensive sequence similarity with the C-terminus of myospryn...
July 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28713282/the-n-terminal-region-of-the-ryanodine-receptor-affects-channel-activation
#2
Andrea Faltinova, Nataša Tomaskova, Marián Antalik, Jozef Sevcik, Alexandra Zahradnikova
Mutations in the cardiac ryanodine receptor (RyR2), the ion channel responsible for release of calcium ions from intracellular stores into cytoplasm, are the cause of several inherited cardiac arrhythmias. At the molecular level, disease symptoms can be mimicked by domain peptides from mutation-prone regions of RyR2 that bind to RyR2 and activate it. Here we show that the domain peptide DPcpvtN2, corresponding to the central helix of the N-terminal region of RyR2, activates the RyR2 channel. Structural modeling of interaction between DPcpvtN2 and the N-terminal region of RyR2 in the closed and open conformation provided three plausible structures of the complex...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28687594/reduced-threshold-for-store-overload-induced-ca-2-release-is-a-common-defect-of-ryr1-mutations-associated-with-malignant-hyperthermia-and-central-core-disease
#3
Wenqian Chen, Andrea Koop, Yingjie Liu, Wenting Guo, Jinhong Wei, Ruiwu Wang, David H MacLennan, Robert T Dirksen, S R Wayne Chen
Mutations in the skeletal muscle ryanodine receptor (RyR1) cause malignant hyperthermia (MH) and central core disease (CCD), while mutations in the cardiac ryanodine receptor (RyR2) lead to catecholaminergic polymorphic ventricular tachycardia (CPVT). Most disease-associated RyR1 and RyR2 mutations are located in the N-terminal, central, and C-terminal regions of the corresponding RyR isoform. An increasing body of evidence demonstrates that CPVT-associated RyR2 mutations enhance the propensity for spontaneous Ca(2+) release during store Ca(2+) overload, a process known as store-overload induced Ca(2+) release (SOICR)...
July 7, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28665545/inhibition-of-mevalonate-pathway-prevents-ischemia-induced-cardiac-dysfunction-in-rats-via-rhoa-independent-signaling-pathway
#4
Ying Yang, Xiqing Rong, Xue Lv, Wenbing Jiang, Yuan Yang, Dongwu Lai, Shiming Xu, Guosheng Fu
AIM: We previously demonstrated that anoxia-mediated Ca(2+) handling dysfunction could be ameliorated through inhibition of mevalonate pathway via RhoA- and Ras-related mechanisms in H9c2 cells. In this study, we further explored whether inhibition of mevalonate pathway is associated with cardiac remodeling and dysfunction in ischemic cardiomyopathy, and discuss the possible role of Ras, Rac and RhoA in cardiac dysfunction. METHODS: We investigated the role of mevalonate pathway in cardiac remodeling and cardiomyocyte Ca(2+) handling proteins expression in a rat model of cardiac dysfunction due to myocardial infarction (MI)...
June 30, 2017: Cardiovascular Therapeutics
https://www.readbyqxmd.com/read/28657075/bioinspired-onion-epithelium-like-structure-promotes-the-maturation-of-cardiomyocytes-derived-from-human-pluripotent-stem-cells
#5
Cong Xu, Li Wang, Yue Yu, Fangchao Yin, Xiaoqing Zhang, Lei Jiang, Jianhua Qin
Organized cardiomyocyte alignment is critical to maintain the mechanical properties of the heart. In this study, we present a new and simple strategy to fabricate a biomimetic microchip designed with an onion epithelium-like structure and investigate the guided behavior of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) on the substrate. The hiPSC-CMs were observed to be confined by the three dimensional surficial features morphologically, analogous to the in vivo microenvironment, and exhibited an organized anisotropic alignment on the onion epithelium-like structure with good beating function...
June 28, 2017: Biomaterials Science
https://www.readbyqxmd.com/read/28638869/reducing-toxicity-and-increasing-efficiency-aconitine-with-liquiritin-and-glycyrrhetinic-acid-regulate-calcium-regulatory-proteins-in-rat-myocardial-cell
#6
Yuyan Zhang, Li Yu, Weifeng Jin, Hongjing Fan, Min Li, Tianmei Zhou, Haitong Wan, Jiehong Yang
BACKGROUND: Compatibility of Radix Aconiti Carmichaeli and Liquorice is known to treat heart diseases such as heart failure and cardiac arrhythmias. This work answers the question that whether the active components (Aconitine, Liquiritin and Glycyrrhetinic Acid) of Radix Aconiti Carmichaeli and Liquorice could result in regulating intracellular calcium homeostasis and calcium cycling, and thereby verifies the therapeutic material basis. MATERIALS AND METHODS: The myocardial cells were divided into twelve groups randomly as control group, Aconitine group, nine different dose groups that orthogonal combined with Aconitine, Liquiritin and Glycyrrhetinic Acid, and Verapamil group...
2017: African Journal of Traditional, Complementary, and Alternative Medicines: AJTCAM
https://www.readbyqxmd.com/read/28631094/post-translational-remodeling-of-ryanodine-receptor-induces-calcium-leak-leading-to-alzheimer-s-disease-like-pathologies-and-cognitive-deficits
#7
Alain Lacampagne, Xiaoping Liu, Steven Reiken, Renaud Bussiere, Albano C Meli, Inger Lauritzen, Andrew F Teich, Ran Zalk, Nathalie Saint, Ottavio Arancio, Charlotte Bauer, Fabrice Duprat, Clark A Briggs, Shreaya Chakroborty, Grace E Stutzmann, Michael L Shelanski, Frederic Checler, Mounia Chami, Andrew R Marks
The mechanisms underlying ryanodine receptor (RyR) dysfunction associated with Alzheimer disease (AD) are still not well understood. Here, we show that neuronal RyR2 channels undergo post-translational remodeling (PKA phosphorylation, oxidation, and nitrosylation) in brains of AD patients, and in two murine models of AD (3 × Tg-AD, APP (+/-) /PS1 (+/-)). RyR2 is depleted of calstabin2 (KFBP12.6) in the channel complex, resulting in endoplasmic reticular (ER) calcium (Ca(2+)) leak. RyR-mediated ER Ca(2+) leak activates Ca(2+)-dependent signaling pathways, contributing to AD pathogenesis...
June 19, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28630041/dysregulated-zn-2-homeostasis-impairs-cardiac-type-2-ryanodine-receptor-and-mitsugumin-23-functions-leading-to-sarcoplasmic-reticulum-ca-2-leakage
#8
Benedict Reilly-O'Donnell, Gavin B Robertson, Angela Karumbi, Connor McIntyre, Wojciech Bal, Miyuki Nishi, Hiroshi Takeshima, Alan J Stewart, Samantha J Pitt
Aberrant Zn2+-homeostasis is associated with dysregulated intracellular Ca2+ release resulting in chronic heart failure. In the failing heart, a small population of cardiac ryanodine receptors (RyR2) display sub-conductance state gating leading to Ca2+ leakage from sarcoplasmic reticulum (SR) stores, which impairs cardiac contractility. Previous evidence suggests contribution of RyR2-independent Ca2+ leakage through an uncharacterized mechanism. We sought to examine the role of Zn2+ in shaping intracellular Ca2+ release in cardiac muscle...
June 19, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28620067/allele-specific-silencing-of-mutant-mrna-rescues-ultrastructural-and-arrhythmic-phenotype-in-mice-carriers-of-the-r4496c-mutation-in-the-ryanodine-receptor-gene-ryr2
#9
Rossana Bongianino, Marco Denegri, Andrea Mazzanti, Francesco Lodola, Alessandra Vollero, Simona Boncompagni, Silvia Fasciano, Giulia Rizzo, Damiano Mangione, Serena Barbaro, Alessia Di Fonso, Carlo Napolitano, Alberto Auricchio, Feliciano Protasi, Silvia G Priori
Rationale: Mutations in the cardiac Ryanodine Receptor gene (RYR2) cause dominant Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), a leading cause of sudden death in apparently healthy individuals exposed to emotions or physical exercise. Objective: We investigated the efficacy of allele specific silencing by RNA interference to prevent CPVT phenotypical manifestations in our dominant CPVT mice model carriers of the heterozygous mutation R4496C in RYR2Methods and Results: We developed an in vitro mRNA and protein-based assays to screen multiple siRNAs for their ability to selectively silence mutant RYR2-R4496C mRNA over the corresponding wild-type (WT) allele...
June 15, 2017: Circulation Research
https://www.readbyqxmd.com/read/28612155/the-role-of-spatial-organization-of-ca-2-release-sites-in-the-generation-of-arrhythmogenic-diastolic-ca-2-release-in-myocytes-from-failing-hearts
#10
Andriy E Belevych, Hsiang-Ting Ho, Ingrid M Bonilla, Radmila Terentyeva, Karsten E Schober, Dmitry Terentyev, Cynthia A Carnes, Sándor Györke
In heart failure (HF), dysregulated cardiac ryanodine receptors (RyR2) contribute to the generation of diastolic Ca(2+) waves (DCWs), thereby predisposing adrenergically stressed failing hearts to life-threatening arrhythmias. However, the specific cellular, subcellular, and molecular defects that account for cardiac arrhythmia in HF remain to be elucidated. Patch-clamp techniques and confocal Ca(2+) imaging were applied to study spatially defined Ca(2+) handling in ventricular myocytes isolated from normal (control) and failing canine hearts...
July 2017: Basic Research in Cardiology
https://www.readbyqxmd.com/read/28587810/subcellular-localization-of-na-k-atpase-isoforms-in-ventricular-myocytes
#11
Garrick K Yuen, Samuel Galice, Donald M Bers
The sodium/potassium ATPase (NKA) is essential for establishing the normal intracellular [Na(+)] and [K(+)] and transmembrane gradients that are essential for many cellular functions, including cardiac electrophysiology and contractility. Different NKA isoforms exhibit differential expression levels, cellular localization, and function in different tissues and species. Prior work has indicated that the NKA-α1 isoform is quantitatively predominant in cardiac myocytes, but that the α2 isoform is preferentially concentrated in the transverse tubules (TT), possibly at junctions with the sarcoplasmic reticulum (SR) where α2 may preferentially modulate cardiac contractility...
June 3, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28584051/ion-pulling-simulations-provide-insights-into-the-mechanisms-of-channel-opening-of-the-skeletal-muscle-ryanodine-receptor
#12
David D Mowrey, Le Xu, Yingwu Mei, Daniel A Pasek, Gerhard Meissner, Nikolay V Dokholyan
The type 1 ryanodine receptor (RyR1) mediates Ca(2+) release from the sarcoplasmic reticulum to initiate skeletal muscle contraction and is associated with muscle diseases, malignant hyperthermia, and central core disease. To better understand RyR1 channel function, we investigated the molecular mechanisms of channel gating and ion permeation. An adequate model of channel gating requires accurate, high-resolution models of both open and closed states of the channel. To this end, we generated an open-channel RyR1 model using molecular simulations to pull Ca(2+) through the pore constriction site of a closed-channel RyR1 structure determined at 3...
June 5, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28573136/effects-of-wenxin-keli-on-cardiac-hypertrophy-and-arrhythmia-via-regulation-of-the-calcium-calmodulin-dependent-kinase-ii-signaling-pathway
#13
Xinyu Yang, Yu Chen, Yanda Li, Xiaomeng Ren, Yanwei Xing, Hongcai Shang
We investigated the effects of Wenxin Keli (WXKL) on the Calcium/Calmodulin dependent kinase II (CaMK II) signal transduction pathway with transverse aortic constriction (TAC) rats. Echocardiographic measurements were obtained 3 and 9 weeks after the surgery. Meanwhile, the action potentials (APDs) were recorded using the whole-cell patch clamp technique, and western blotting was used to assess components of the CaMK II signal transduction pathway. At both 3 and 9 weeks after treatment, the fractional shortening (FS%) increased in the WXKL group compared with the TAC group...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28536695/cardiac-protection-of-valsartan-on-juvenile-rats-with-heart-failure-by-inhibiting-activity-of-camkii-via-attenuating-phosphorylation
#14
Yao Wu, Feifei Si, Xiaojuan Ji, Kunfeng Jiang, Sijie Song, Qijian Yi
Background. This study was undertaken to determine relative contributions of phosphorylation and oxidation to the increased activity of calcium/calmodulin-stimulated protein kinase II (CaMKII) in juveniles with cardiac myocyte dysfunction due to increased pressure overload. Methods. Juvenile rats underwent abdominal aortic constriction to induce heart failure. Four weeks after surgery, rats were then randomly divided into two groups: one group given valsartan (HF + Val) and the other group given placebo (HF + PBO)...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28536302/a-cryo-em-based-model-of-phosphorylation-and-fkbp12-6-mediated-allosterism-of-the-cardiac-ryanodine-receptor
#15
Sonali Dhindwal, Joshua Lobo, Vanessa Cabra, Demetrio J Santiago, Ashok R Nayak, Kelly Dryden, Montserrat Samsó
Type 2 ryanodine receptors (RyR2s) are calcium channels that play a vital role in triggering cardiac muscle contraction by releasing calcium from the sarcoplasmic reticulum into the cytoplasm. Several cardiomyopathies are associated with the abnormal functioning of RyR2. We determined the three-dimensional structure of rabbit RyR2 in complex with the regulatory protein FKBP12.6 in the closed state at 11.8 Å resolution using cryo-electron microscopy and built an atomic model of RyR2. The heterogeneity in the data set revealed two RyR2 conformations that we proposed to be related to the extent of phosphorylation of the P2 domain...
May 23, 2017: Science Signaling
https://www.readbyqxmd.com/read/28536299/new-connections-how-to-become-more-flexible-and-open-up
#16
Wei Wong
Cryo-EM-generated structures provide insight into how RyR2 is gated and how phosphorylation may affect the activation process.
May 23, 2017: Science Signaling
https://www.readbyqxmd.com/read/28508509/investigating-the-inter-subunit-subdomain-interactions-and-motions-relevant-to-disease-mutations-in-the-n-terminal-domain-of-ryanodine-receptors-by-molecular-dynamics-simulation
#17
Wenjun Zheng, Zheng Liu
The ryanodine receptors (RyR) are essential to calcium signaling in striated muscles, and numerous disease mutations have been identified in two RyR isoforms, RyR1 in skeletal muscle and RyR2 in cardiac muscle. A deep understanding of the activation/regulation mechanisms of RyRs has been hampered by the shortage of high-resolution structures and dynamic information for this giant tetrameric complex in different functional states. Toward elucidating the molecular mechanisms of disease mutations in RyRs, we performed molecular dynamics simulation of the N-terminal domain (NTD) which is not only the best-resolved structural component of RyRs, but also a hotspot of disease mutations...
May 15, 2017: Proteins
https://www.readbyqxmd.com/read/28487634/ryr2-mediated-ca-2-release-and-mitochondrial-ros-generation-partake-in-the-synaptic-dysfunction-caused-by-amyloid-%C3%AE-peptide-oligomers
#18
Carol D SanMartín, Pablo Veloso, Tatiana Adasme, Pedro Lobos, Barbara Bruna, Jose Galaz, Alejandra García, Steffen Hartel, Cecilia Hidalgo, Andrea C Paula-Lima
Amyloid β peptide oligomers (AβOs), toxic aggregates with pivotal roles in Alzheimer's disease, trigger persistent and low magnitude Ca(2+) signals in neurons. We reported previously that these Ca(2+) signals, which arise from Ca(2+) entry and subsequent amplification by Ca(2+) release through ryanodine receptor (RyR) channels, promote mitochondrial network fragmentation and reduce RyR2 expression. Here, we examined if AβOs, by inducing redox sensitive RyR-mediated Ca(2+) release, stimulate mitochondrial Ca(2+)-uptake, ROS generation and mitochondrial fragmentation, and also investigated the effects of the antioxidant N-acetyl cysteine (NAC) and the mitochondrial antioxidant EUK-134 on AβOs-induced mitochondrial dysfunction...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28484388/aging-impairs-hippocampal-dependent-recognition-memory-and-ltp-and-prevents-the-associated-ryr-up-regulation
#19
Alejandra Arias-Cavieres, Tatiana Adasme, Gina Sánchez, Pablo Muñoz, Cecilia Hidalgo
Recognition memory comprises recollection judgment and familiarity, two different processes that engage the hippocampus and the perirhinal cortex, respectively. Previous studies have shown that aged rodents display defective recognition memory and alterations in hippocampal synaptic plasticity. We report here that young rats efficiently performed at short-term (5 min) and long-term (24 h) hippocampus-associated object-location tasks and perirhinal cortex-related novel-object recognition tasks. In contrast, aged rats successfully performed the object-location and the novel-object recognition tasks only at short-term...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28476886/amyloid-%C3%AE-production-is-regulated-by-%C3%AE-2-adrenergic-signaling-mediated-post-translational-modifications-of-the-ryanodine-receptor
#20
Renaud Bussiere, Alain Lacampagne, Steven Reiken, Xiaoping Liu, Valerie Scheuerman, Ran Zalk, Cécile Martin, Frederic Checler, Andrew R Marks, Mounia Chami
Alteration of ryanodine receptor (RyR)-mediated calcium (Ca(2+)) signaling has been reported in Alzheimer disease (AD) models. However, the molecular mechanisms underlying altered RyR-mediated intracellular Ca(2+) release in AD remain to be fully elucidated. We report here that RyR2 undergoes post-translational modifications (phosphorylation, oxidation, and nitrosylation) in SH-SY5Y neuroblastoma cells expressing the β-amyloid precursor protein (βAPP) harboring the familial double Swedish mutations (APPswe)...
June 16, 2017: Journal of Biological Chemistry
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