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("ryanodine receptor" OR "ryr" OR "ryr2") AND ("heart" OR "cardiac")

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https://www.readbyqxmd.com/read/28550171/%C3%AE-adrenergic-receptor-stimulation-inhibits-proarrhythmic-alternans-in-post-infarction-border-zone-cardiomyocytes-a-computational-analysis
#1
Jakub Tomek, Blanca Rodriguez, Gil Bub, Jordi Heijman
The border zone (BZ) of viable myocardium adjacent to an infarct undergoes extensive autonomic and electrical remodelling and is prone to repolarisation alternans-induced cardiac arrhythmias. BZ remodelling processes may promote or inhibit calcium and/or repolarisation alternans and may differentially affect ventricular arrhythmogenesis. Here, we employed a detailed computational model of the canine ventricular cardiomyocyte to study the determinants of alternans in the BZ and their regulation by β-adrenergic receptor (βAR) stimulation...
May 26, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28538150/lanthanides-report-calcium-sensor-in-the-vestibule-of-ryanodine-receptor
#2
Sándor Sárközi, István Komáromi, István Jóna, János Almássy
Ca(2+) regulates ryanodine receptor's (RyR) activity through an activating and an inhibiting Ca(2+)-binding site located on the cytoplasmic side of the RyR channel. Their altered sensitivity plays an important role in the pathology of malignant hyperthermia and heart failure. We used lanthanide ions (Ln(3+)) as probes to investigate the Ca(2+) sensors of RyR, because they specifically bind to Ca(2+)-binding proteins and they are impermeable to the channel. Eu(3+)'s and Sm(3+)'s action was tested on single RyR1 channels reconstituted into planar lipid bilayers...
May 23, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28536695/cardiac-protection-of-valsartan-on-juvenile-rats-with-heart-failure-by-inhibiting-activity-of-camkii-via-attenuating-phosphorylation
#3
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
#4
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/28528672/physiology-and-pharmacology-of-ryanodine-receptor-calcium-release-channels
#5
Angela F Dulhunty, Philip G Board, Nicole A Beard, Marco G Casarotto
Ryanodine receptor (RyR) ion channels are essential for skeletal and cardiac muscle function. Their knockout leads to perinatal death from respiratory and cardiac failure. Acquired changes or mutations in the protein cause debilitating skeletal myopathy and cardiac arrhythmia which can be deadly. Knowledge of the pharmacology of RyR channels is central to developing effective and specific treatments of these myopathies. The ion channel is a >2.2MDa homotetamer with distinct structural and functional characteristics giving rise to a myriad of regulatory sites that are potential therapeutic targets...
2017: Advances in Pharmacology
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
#6
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/28506910/omecamtiv-mecarbil-activates-ryanodine-receptors-from-canine-cardiac-but-not-skeletal-muscle
#7
Péter Nánási, Marta Gaburjakova, Jana Gaburjakova, János Almássy
Due to the limited results achieved in the clinical treatment of heart failure, a new inotropic strategy of myosin motor activation has been developed. The lead molecule of myosin activator agents is omecamtiv mecarbil, which binds directly to the heavy chain of the cardiac β-myosin and enhances cardiac contractility by lengthening the lifetime of the acto-myosin complex and increasing the number of the active force-generating cross-bridges. In the absence of relevant data, the effect of omecamtiv mecarbil on canine cardiac ryanodine receptors (RyR 2) has been investigated in the present study by measuring the electrical activity of single RyR 2 channels incorporated into planar lipid bilayer...
May 12, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28499500/ca-2-release-channels-join-the-resolution-revolution
#8
REVIEW
Ran Zalk, Andrew R Marks
Ryanodine receptors (RyRs) are calcium release channels expressed in the sarcoendoplasmic reticula of many cell types including cardiac and skeletal muscle cells. In recent years Ca(2+) leak through RyRs has been implicated as a major contributor to the development of diseases including heart failure, muscle myopathies, Alzheimer's disease, and diabetes, making it an important therapeutic target. Recent mammalian RyR1 cryoelectron microscopy (cryo-EM) structures of multiple functional states have clarified longstanding questions including the architecture of the transmembrane (TM) pore and cytoplasmic domains, the location and architecture of the channel gate, ligand-binding sites, and the gating mechanism...
May 9, 2017: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/28497395/cardio-protective-effects-of-qishen-granule-on-sarcoplasmic-reticulum-ca-2-handling-in-heart-failure-rats
#9
Ling-Hui Lu, Chun Li, Qi-Yan Wang, Qian Zhang, Yi Zhang, Hui Meng, Yong Wang, Wei Wang
OBJECTIVES: To assess the effects of Qishen Granule (, QSG) on sarcoplasmic reticulum (SR) Ca(2+) handling in heart failure (HF) model of rats and to explore the underlying molecular mechanisms. METHODS: HF rat models were induced by left anterior descending coronary artery ligation surgery and high-fat diet feeding. Rats were randomly divided into sham (n=10), model (n=10), QSG (n=12, 2.2 g/kg daily) and metoprolol groups (n=12, 10.5 mg/kg daily). The therapeutic effects of QSG were evaluated by echocardiography and blood lipid testing...
May 11, 2017: Chinese Journal of Integrative Medicine
https://www.readbyqxmd.com/read/28487342/calcium-calmodulin-dependent-protein-kinase-ii-activity-persists-during-chronic-%C3%AE-adrenoceptor-blockade-in-experimental-and-human-heart-failure
#10
Matthias Dewenter, Stefan Neef, Christiane Vettel, Simon Lämmle, Christina Beushausen, Laura C Zelarayan, Sylvia Katz, Albert von der Lieth, Stefanie Meyer-Roxlau, Silvio Weber, Thomas Wieland, Samuel Sossalla, Johannes Backs, Joan H Brown, Lars S Maier, Ali El-Armouche
BACKGROUND: Considerable evidence suggests that calcium/calmodulin-dependent protein kinase II (CaMKII) overactivity plays a crucial role in the pathophysiology of heart failure (HF), a condition characterized by excessive β-adrenoceptor (β-AR) stimulation. Recent studies indicate a significant cross talk between β-AR signaling and CaMKII activation presenting CaMKII as a possible downstream mediator of detrimental β-AR signaling in HF. In this study, we investigated the effect of chronic β-AR blocker treatment on CaMKII activity in human and experimental HF...
May 2017: Circulation. Heart Failure
https://www.readbyqxmd.com/read/28476922/sarcolemmal-distribution-of-ica-and-incx-and-ca-autoregulation-in-mouse-ventricular-myocytes
#11
Hanne C Gadeberg, Cherrie H T Kong, Simon M Bryant, Andrew F James, Clive H Orchard
The balance of Ca influx and efflux regulates the Ca load of cardiac myocytes, a process known as autoregulation. Previous work has shown that Ca influx, via L-type Ca current (ICa), and efflux, via Na-Ca exchange (NCX), occur predominantly at t-tubules; however the role of t-tubules in autoregulation is unknown. We therefore investigated the sarcolemmal distribution of ICa and INCX, and autoregulation, in mouse ventricular myocytes using whole cell voltage-clamp and simultaneous Ca measurement in intact and detubulated (DT) cells...
May 5, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28476660/%C3%AE-adrenergic-induced-sr-ca-2-leak-is-mediated-by-an-epac-nos-pathway
#12
Laëtitia Pereira, Dan J Bare, Samuel Galice, Thomas R Shannon, Donald M Bers
Cardiac β-adrenergic receptors (β-AR) and Ca(2+)-Calmodulin dependent protein kinase (CaMKII) regulate both physiological and pathophysiological Ca(2+) signaling. Elevated diastolic Ca(2+) leak from the sarcoplasmic reticulum (SR) contributes to contractile dysfunction in heart failure and to arrhythmogenesis. β-AR activation is known to increase SR Ca(2+) leak via CaMKII-dependent phosphorylation of the ryanodine receptor. Two independent and reportedly parallel pathways have been implicated in this β-AR-CaMKII cascade, one involving exchange protein directly activated by cAMP (Epac2) and another involving nitric oxide synthase 1 (NOS1)...
May 2, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28473402/post-myocardial-infarction-t-tubules-form-enlarged-branched-structures-with-dysregulation-of-junctophilin-2-and-bridging-integrator-1-bin-1
#13
Christian Pinali, Nadim Malik, J Bernard Davenport, Laurence J Allan, Lucy Murfitt, Mohammad M Iqbal, Mark R Boyett, Elizabeth J Wright, Rachel Walker, Yu Zhang, Halina Dobryznski, Cathy M Holt, Ashraf Kitmitto
BACKGROUND: Heart failure is a common secondary complication following a myocardial infarction (MI), characterized by impaired cardiac contraction and t-tubule (t-t) loss. However, post-MI nano-scale morphological changes to the remaining t-ts are poorly understood. METHOD AND RESULTS: We utilized a porcine model of MI, using a nonlethal microembolization method to generate controlled microinfarcts. Using serial block face scanning electron microscopy, we report that post-MI, after mild left-ventricular dysfunction has developed, t-ts are not only lost in the peri-infarct region, but also the remnant t-ts form enlarged, highly branched disordered structures, containing a dense intricate inner membrane...
May 4, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28469494/studying-dyadic-structure-function-relationships-a-review-of-current-modeling-approaches-and-new-insights-into-ca-2-mis-handling
#14
Mary M Maleckar, Andrew G Edwards, William E Louch, Glenn T Lines
Excitation-contraction coupling in cardiac myocytes requires calcium influx through L-type calcium channels in the sarcolemma, which gates calcium release through sarcoplasmic reticulum ryanodine receptors in a process known as calcium-induced calcium release, producing a myoplasmic calcium transient and enabling cardiomyocyte contraction. The spatio-temporal dynamics of calcium release, buffering, and reuptake into the sarcoplasmic reticulum play a central role in excitation-contraction coupling in both normal and diseased cardiac myocytes...
2017: Clinical Medicine Insights. Cardiology
https://www.readbyqxmd.com/read/28453742/blinded-contractility-analysis-in-hipsc-cardiomyocytes-in-engineered-heart-tissue-format-comparison-with-human-atrial-trabeculae
#15
Ingra Mannhardt, Alexandra Eder, Berengere Dumotier, Maksymilian Prondzynski, Elisabeth Krämer, Martin Traebert, Klaus-Dieter Söhren, Frederik Flenner, Konstantina Stathopoulou, Marc D Lemoine, Lucie Carrier, Torsten Christ, Thomas Eschenhagen, Arne Hansen
Objective: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) may serve as a new assay for drug testing in a human context, but their validity particularly for the evaluation of inotropic drug effects remains unclear. In this blinded analysis, we compared the effects of 10 indicator compounds with known inotropic effects in electrically stimulated (1.5 Hz) hiPSC-CM-derived 3 dimensional engineered heart tissue (EHT) and human atrial trabeculae (hAT). Methods and results: Human EHTs were prepared from iCell® hiPSC-CM, hAT obtained at routine heart surgery...
April 27, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28451724/chronic-loss-of-inhibitor-1-diminishes-cardiac-ryr2-phosphorylation-despite-exaggerated-camkii-activity
#16
Stefan Neef, Jordi Heijman, Kristian Otte, Matthias Dewenter, Ali R Saadatmand, Stefanie Meyer-Roxlau, Christopher L Antos, Johannes Backs, Dobromir Dobrev, Michael Wagner, Lars S Maier, Ali El-Armouche
Inhibitor-1 (I-1) modulates protein phosphatase 1 (PP1) activity and thereby counteracts the phosphorylation by kinases. I-1 is downregulated and deactivated in failing hearts, but whether its role is beneficial or detrimental remains controversial, and opposing therapeutic strategies have been proposed. Overactivity of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) with hyperphosphorylation of ryanodine receptors (RyR2) at the CaMKII-site is recognized to be central for heart failure and arrhythmias...
April 27, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28449774/utility-of-post-mortem-genetic-testing-in-cases-of-sudden-arrhythmic-death-syndrome
#17
Najim Lahrouchi, Hariharan Raju, Elisabeth M Lodder, Efstathios Papatheodorou, James S Ware, Michael Papadakis, Rafik Tadros, Della Cole, Jonathan R Skinner, Jackie Crawford, Donald R Love, Chee J Pua, Bee Y Soh, Jaydutt D Bhalshankar, Risha Govind, Jacob Tfelt-Hansen, Bo G Winkel, Christian van der Werf, Yanushi D Wijeyeratne, Greg Mellor, Jan Till, Marta C Cohen, Maria Tome-Esteban, Sanjay Sharma, Arthur A M Wilde, Stuart A Cook, Connie R Bezzina, Mary N Sheppard, Elijah R Behr
BACKGROUND: Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology. OBJECTIVES: This study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives. METHODS: We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes...
May 2, 2017: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/28443506/catestain-a-master-regulator-of-cardiovascular-functions
#18
Sushil K Mahata, Malapaka Kiranmayi, Nitish R Mahapatra
Cardiovascular disease (CVD), the most common cause of death globally, accounts for ~30% of all deaths worldwide. Hypertension is a common contributor to morbidity and mortality from CVD. The plasma concentration of chromogranin A (CgA) is elevated in patients with CVD as well as patients with established human essential hypertension and heart failure (HF). In contrast, the plasma level of the CgA-derived peptide catestatin (CST) is diminished in human essential hypertension. Low conversion of CgA-to-CST has been associated with increased mortality in patients hospitalized with acute HF...
April 24, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28428008/force-development-and-intracellular-ca-2-in-intact-cardiac-muscles-from-gravin-mutant-mice
#19
Zhitao Li, Sonal Singh, Santosh V Suryavanshi, Wengang Ding, Xiaoxu Shen, Cori S Wijaya, Wei Dong Gao, Bradley K McConnell
Gravin (AKAP12) is an A-kinase-anchoring-protein that scaffolds protein kinase A (PKA), β2-adrenergic receptor (β2-AR), protein phosphatase 2B and protein kinase C. Gravin facilitates β2-AR-dependent signal transduction through PKA to modulate cardiac excitation-contraction coupling and its removal positively affects cardiac contraction. Trabeculae from the right ventricles of gravin mutant (gravin-t/t) mice were employed for force determination. Simultaneously, corresponding intracellular Ca(2+) transient ([Ca(2+)]i) were measured...
April 17, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28422759/ryr2r420q-catecholaminergic-polymorphic-ventricular-tachycardia-mutation-induces-bradycardia-by-disturbing-the-coupled-clock-pacemaker-mechanism
#20
Yue Yi Wang, Pietro Mesirca, Elena Marqués-Sulé, Alexandra Zahradnikova, Olivier Villejoubert, Pilar D'Ocon, Cristina Ruiz, Diana Domingo, Esther Zorio, Matteo E Mangoni, Jean-Pierre Benitah, Ana María Gómez
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal genetic arrhythmia that manifests syncope or sudden death in children and young adults under stress conditions. CPVT patients often present bradycardia and sino-atrial node (SAN) dysfunction. However, the mechanism remains unclear. We analyzed SAN function in two CPVT families and in a novel knock-in (KI) mouse model carrying the RyR2R420Q mutation. Humans and KI mice presented slower resting heart rate. Accordingly, the rate of spontaneous intracellular Ca2+ ([Ca2+]i) transients was slower in KI mouse SAN preparations than in WT, without any significant alteration in the "funny" current (If )...
April 20, 2017: JCI Insight
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