1. Propranolol, a β-blocker, inhibited or stimulated ryanodine binding to both the membrane-bound and purified ryanodine receptor (RyR) depending on the assay conditions. At high NaCl concentrations, propranolol increased the number of ryanodine-binding sites (Bmax) with no effect on the binding affinity. In the presence of 0.2 M NaCl, ryanodine binding was inhibited by propranolol. Half-maximal inhibition was obtained at 1.2 mM and complete inhibition at 2 mM propranolol. The inhibitory effect of propranolol obtained at low NaCl concentration was not restored by increasing the NaCl concentration to 1 M. 2. Modulators of the RyR that are known to alter its conformational states, such as adenine nucleotides, Ca2+ concentration and pH, modified the effect of propranolol on ryanodine binding. In the presence of propranolol and at low NaCl concentrations, ryanodine binding was inhibited and showed no Ca2+-, pH- or time-dependence. 3. Propranolol immediately and completely blocked the channel ...

The potentiatory effects of CASQ2 on the Ca2+-release channels were evidenced by the following findings. Expression of CASQ2R33Q resulted in a shortening of the activation kinetics of Ca2+ transients, and increased CICR gain compared with control myocytes or myocytes overexpressing CASQ2WT. Additionally, the frequency of spontaneous Ca2+ sparks and waves were increased in myocytes expressing CASQ2R33Q. These changes in focal and global cytosolic Ca2+ transients were accompanied by a dramatic decrease in intra-SR [Ca2+], consistent with an increase in the leak of Ca2+ through RyR2s in CASQ2R33Q-expressing cells. The consequences of expressing CASQ2R33Q on Ca2+ handling were clearly different from the effects of expressing the CASQ2D307H mutant protein, the only other CPVT-linked CASQ2 mutation that has been characterized at the cellular and molecular level thus far.16,17 In those earlier studies, ectopic expression of CASQ2D307H in myocytes led to decreases in both active SR Ca2+ release and SR ...

The calcium release channel (CRC) from skeletal muscle is an unusually large tetrameric ion channel of the sarcoplasmic reticulum, and it is a major component of the triad junction, the site of excitation contraction coupling. The three-dimensional architecture of the CRC was determined from a random conical tilt series of images extracted from electron micrographs of isolated detergent-solubilized channels prepared in a frozen-hydrated state. Three major classes of fourfold symmetric images were identified, and three-dimensional reconstructions were determined for two of these. The two independent reconstructions were almost identical, being related to each other by a 180 degrees rotation about an axis in the plane of the specimen grid. The CRC consists of a large cytoplasmic assembly (29 x 29 x 12 nm) and a smaller transmembrane assembly that protrudes 7 nm from one of its faces. A cylindrical low-density region, 2-3 nm in apparent diameter, extends down the center of the transmembrane ...

Ryanodine receptors (RyRs) form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons. There are three major isoforms of the ryanodine receptor, which are found in different tissues and participate in different signaling pathways involving calcium release from intracellular organelles. The RYR2 ryanodine receptor isoform is the major cellular mediator of calcium-induced calcium release (CICR) in animal cells. The ryanodine receptors are named after the plant alkaloid ryanodine, to which they show a high affinity. There are multiple isoforms of ryanodine receptors: RyR1 is primarily expressed in skeletal muscle RyR2 is primarily expressed in myocardium (heart muscle) RyR3 is expressed more widely, but especially in the brain. Non-mammalian vertebrates typically express two RyR isoforms, referred to as RyR-alpha and RyR-beta. Many invertebrates, including the model organisms Drosophila melanogaster (fruitfly) and Caenorhabditis elegans, only ...

We have tested the periodate-oxidized ATP analogue 2′,3′-dialdehyde adenosine triphosphate (oATP) as a ligand for the skeletal muscle ryanodine receptor/Ca(2+)-release channel. Ca2+ efflux from passively loaded heavy sarcoplasmic reticulum vesicles of skeletal muscle is biphasic. oATP stimulates the initial phase of Ca2+ release in a concentration-dependent manner (EC50 160 microM), and the efflux proceeds with a half-time in the range 100-200 ms. This oATP-modulated initial rapid Ca2+ release was specifically inhibited by millimolar concentrations of Mg2+ and micromolar concentrations of Ruthenium Red, indicating that the effect of oATP was mediated via the ryanodine receptor. The purified Ca(2+)-release channel was incorporated into planar lipid bilayers, and single-channel recordings were carried out to verify a direct interaction of oATP with the ryanodine receptor. Addition of oATP to the cytoplasmic side activated the channel with an EC50 of 76 microM, which is roughly 30-fold higher ...

Thymomas are associated with red cell aplasia and in 50 %, with MG. Some patients with MG have inflammatory myopathy of striated and cardiac muscle. Diagnosis is with prosimal muscle weakness, high CPK levels, and myopathic EMG. Cardiac myositis leads to CHF, arrythmia, and sudden death. Patients with thymoma also may have neuromyotonia (NMT) with hyperactive peripheral motor nerves, myokymia, muscle stiffness, cramps, hypertrophy. EMG shows bursts of high frequency motor unit discharges. Antibodies against VGKC have been detected in NMT with or without thymoma. Other antibodies seen are against skeletal muscle calcium release channel (ryanodine receptor RyR) of sarcoplasmic reticulum; and antibodies to cytoplasmic filaments titin or neurofilaments ...

We have used tryptic digestion to determine whether Ca(2+) can regulate cardiac ryanodine receptor (RyR) channel gating from within the lumen of the sarcoplasmic reticulum (SR) or whether Ca(2+) must first flow through the channel and act via cytosolically located binding sites. Cardiac RyRs were incorporated into bilayers, and trypsin was applied to the luminal side of the bilayer. We found that before exposure to luminal trypsin, the open probability of RyR was increased by raising the luminal [Ca(2+)] from 10 micromol/L to 1 mmol/L, whereas after luminal trypsin exposure, increasing the luminal [Ca(2+)] reduced the open probability. The modification in the response of RyRs to luminal Ca(2+) was not observed with heat-inactivated trypsin, indicating that digestion of luminal sites on the RyR channel complex was responsible. Our results provide strong evidence for the presence of luminally located Ca(2+) activation and inhibition sites and indicate that trypsin digestion leads to selective damage to

Chronic anthracycline administration to rabbits causes impairment of cardiac contractility and decreased gene expression of the calcium-induced calcium release channel of sarcoplasmic reticulum (SR), the ryanodine receptor (RYR2). The C-13 hydroxy me

Ca2+ release from the sarcoplasmic reticulum mediated by the cardiac ryanodine receptor (RyR2) is a fundamental event in cardiac muscle contraction. RyR2 mutations suggested to cause defective Ca2+ channel function have recently been identified in catecholaminergic polymorphic ventricular tachycardia (CPVT) and arrhythmogenic right ventricular dysplasia (ARVD) affected individuals. We report expression of three CPVT-linked human RyR2 (hRyR2) mutations (S2246L, N4104K, and R4497C) in HL-1 cardiomyocytes displaying correct targeting to the endoplasmic reticulum. N4104K also localized to the Golgi apparatus. Phenotypic characteristics including intracellular Ca2+ handling, proliferation, viability, RyR2:FKBP12.6 interaction, and beat rate in resting HL-1 cells expressing mutant hRyR2 were indistinguishable from wild-type (WT) hRyR2. However, Ca2+ release was augmented in cells expressing mutant hRyR2 after RyR activation (caffeine and 4-chloro-m-cresol) or. ...

The Sarcoplasmic Reticulum Calcium ion channel (SR) functions primarily as an intracellular store of calcium in skeletal muscle cells. The SR channel is responsible for the controlled release of calcium in skeletal muscle cells during muscular contraction/relaxation and movement. Due to its high affinity for the plant alkaloid Ryanodine, the SR calcium channel is commonly referred to as the ryanodine receptor (RyR). Presently, three known RyR types have been identified: RyR1, RyR2, and RyR3. The RyR1 type is predominately expressed in skeletal muscles and the cerebellum. The RyR2 type has been observed primarily in cardiac muscle and brain tissues. The RyR3 type shows expression in a variety of tissues. A full-length message has been cloned from a blue marlin cDNA library. A comparison of its amino acid sequence to other known sequences shows this clone to match other previously described RyR isoforms, (Franck et al. , 1998). Two distinct RyR1-like messages have been cloned and characterized in ...

article{33874d02-bd65-463d-be9f-936bcd8cfb6f, abstract = {The block of rabbit skeletal ryanodine receptors (RyR1) and dog heart RyR2 by cytosolic [Mg2+], and its reversal by agonists Ca2+, ATP and caffeine was studied in planar bilayers. Mg2+ effects were tested at submaximal activating [Ca2+] (5 microM). Approximately one third of the RyR1s had low open probability (LA channels) in the absence of Mg2+. All other RyR1s displayed higher activity (HA channels). Cytosolic Mg2+ (1 mM) blocked individual RyR1 channels to varying degrees (32 to 100%). LA channels had residual P(o) <0.005 in 1 mM Mg2+ and reactivated poorly with [Ca2+] (100 microM), caffeine (5 mM), or ATP (4 mM; all at constant 1 mM Mg2+). HA channels had variable activity in Mg2+ and variable degree of recovery from Mg2+ block with Ca2+, caffeine or ATP application. Nearly all cardiac RyR2s displayed high activity in 5 microM [Ca2+]. They also had variable sensitivity to Mg2+. However, the RyR2s consistently recovered from ...

The administration of the ryanodine receptor (RyR) agonist 4-Cmc (0.003-9 nmol per mouse intracerebroventricularly (i.c.v.) ameliorated memory functions, whereas the RyR antagonist ryanodine (0.0001-1 nmol per mouse i.c.v.) induced amnesia in the mouse passive avoidance test. The role of the type 1, 2, and 3 RyR isoforms in memory processes was then evaluated by inhibiting the expression of the three RyR proteins in the mouse brain. A selective knockdown of the RyR isoforms was obtained by the i.c.v. administration of antisense oligonucleotides (aODNs) complementary to the sequence of RyR1, RyR2 and RyR3 proteins, as demonstrated by immunoblotting experiments. RyR1 (5-9 nmol per mouse i.c.v.) knockdown mice did not show any memory dysfunction. Conversely, RyR2 (1-7 nmol per mouse i.c.v.) and RyR3 (1-7 nmol per mouse i.c.v.) knockdown animals showed an impairment of memory processes. This detrimental effect was temporary and reversible, disappearing 7 d after the end of the aODN treatment. At the ...

DUGi: Viewing Item from repository Recercat: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a difficult-to-diagnose cause of sudden cardiac death (SCD). We identified a family of 1400 individuals with multiple cases of CPVT, including 36 SCDs during youth. Objectives: We sought to identify the genetic cause of CPVT in this family, to preventively treat and clinically characterize the mutation-positive individuals, and to functionally characterize the pathogenic mechanisms of the mutation. Methods: Genetic testing was performed for 1404 relatives. Mutation-positive subjects were preventively treated with β-blockers and clinically characterized with a serial exercise treadmill test (ETT) and Holter monitoring. In vitro functional studies included caffeine sensitivity and store overload-induced calcium release activity of the mutant channel in HEK293 cells. Results: We identified the p.G357S_RyR2 mutation, in the cardiac ryanodine receptor, in 179 family members and in 6 SCD victims. No

Purines have to do with both, physiological and pharmacological regulation of the RyR activity. So far, the mechanisms of RyR activation by ATP and caffeine have been described in detail using [3H]-ryanodine binding assays and unitary channel activity recorded in planar lipid bilayers. However, some questions remain to be addressed and are at present aim of active scrutiny: How many sites for purines are present in the RyR? Is the same site recognized by nucleotides and methylxanthines? What differences exist among the interaction between RyR and purine bases, nucleosides and nucleotides? Are the phosphate groups important for the recognition of nucleotides? Is the sugar moiety important for the recognition of nucleosides? The review article will examine the most recent specialized literature about the mechanism of activation of RyR by purines with emphasis on reports with approaches of structure-function and structure-activation ...

Fingerprint Dive into the research topics of Role of cardiac ryanodine receptor calmodulin-binding domains in mediating the action of arrhythmogenic calmodulin N-domain mutation N54I. Together they form a unique fingerprint. ...

The RYR1 functions as the Ca2+ release channel in the skeletal muscle SR. The functional RYR1 SR Ca2+ release channel is a 2.3-megadalton homomeric assembly of four ∼565-kD RYR1 subunits. Each RYR1 subunit is composed of a large N-terminal cytosolic foot region and six to eight transmembrane sequences located within the C-terminal portion of the protein (Du et al., 2002, 2004). By analogy with known K+ channel structures, the selectivity filter of the RYR1 Ca2+ release channel is determined by a conserved hydrophobic sequence Gly-Ile-Gly (amino acids 4894-4895-4896 in mouse RYR1) (Zhao et al., 1999; Gao et al., 2000; Williams et al., 2001) located between the final two transmembrane domains. Fully assembled tetrameric Ca2+ release channels are arranged in regular arrays within the terminal cisternae of the SR (Franzini-Armstrong and Nunzi, 1983; Block et al., 1988; Franzini-Armstrong and Kish, 1995; Protasi et al., 1997). Activation of RYR1 Ca2+ release channels within these arrays during ...

Our data provide the previously missing demonstration that the presence of the R4496C mutation predisposes the murine heart to the development of bidirectional and polymorphic VT and to ventricular fibrillation on administration of caffeine and of adrenergic agonists. Combined with the evidence provided by in vitro characterization of the same RyR2 mutant5-8 it seems plausible to suggest that arrhythmias in the RyR2+/RyRR4496C mice are caused by enhanced calcium release from the sarcoplasmic reticulum through the defective RyR2 channels.. The cardiac ryanodine receptor (RyR2) is a tetrameric intracellular calcium release channel located in the sarcoplasmic reticulum (SR) that has a pivotal role in cardiac excitation-contraction coupling. In response to a small intracellular calcium influx through the L-type voltage dependent calcium channels, RyR2 releases from the SR the large amount of calcium that is needed to elicit contraction of the cardiac cell. However, in addition to such a tightly ...

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Inositol 1,4,5-trisphosphate (IP3) is a ubiquitous intracellular messenger regulating diverse functions in almost all mammalian cell types. It is generated by membrane receptors that couple to phospholipase C (PLC), an enzyme which liberates IP3 from phosphatidylinositol 4,5-bisphosphate (PIP2). The major action of IP3, which is hydrophilic and thus translocates from the membrane into the cytoplasm, is to induce Ca2+ release from endogenous stores through IP3 receptors (IP3Rs). Cardiac excitation-contraction coupling relies largely on ryanodine receptor (RyR)-induced Ca2+ release from the sarcoplasmic reticulum. Myocytes express a significantly larger number of RyRs compared to IP3Rs (~100:1), and furthermore they experience substantial fluxes of Ca2+ with each heartbeat. Therefore, the role of IP3 and IP3-mediated Ca2+ signaling in cardiac myocytes has long been enigmatic. Recent evidence, however, indicates that despite their paucity cardiac IP3Rs may play crucial roles in regulating diverse ...

Postnatal maturation of the rat heart is characterized by major changes in the mechanism of excitation-contraction (E-C) coupling. In the neonate, the t tubules and sarcoplasmic reticulum (SR) are not fully developed yet. Consequently, Ca(2+)-induced Ca(2+) release (CICR) does not play a central role in E-C coupling. In the neonate, most of the Ca(2+) that triggers contraction comes through the sarcolemma. In this work, we defined the contribution of the sarcolemmal Ca(2+) entry and the Ca(2+) released from the SR to the Ca(2+) transient during the first 3 wk of postnatal development. To this end, intracellular Ca(2+) transients were measured in whole hearts from neonate rats by using the pulsed local field fluorescence technique. To estimate the contribution of each Ca(2+) flux to the global intracellular Ca(2+) transient, different pharmacological agents were used. Ryanodine was applied to evaluate ryanodine receptor-mediated Ca(2+) release from the SR, nifedipine for dihydropyridine-sensitive L-type

The ryanodine receptor, which is generally known as a Ca2+-induced Ca2+ release channel of SR (Ebashi, 1991; Sutko and Airey, 1996), may be the machinery of excitation-contraction coupling in skeletal muscle (Ford and Podolsky, 1970; Endo, 1977). Ryanodine was reported to selectively bind to its receptor in an open state. (McPherson and Campbell, 1993). The Ca2+ channel has been purified using [3H]ryanodine as a specific ligand (Inui et al., 1987; Hymel et al., 1988; Wagenknecht et al., 1989). Not only ryanodine but also a variety of natural products, such as imperatoxin (Valdivia et al., 1992) and MBED (Seino et al., 1991), have attracted the attention of pharmacologists, physiologists, and biochemists because they act on their specific binding sites in the ryanodine receptor with high affinity. The function of Ca2+release channels is inhibited by several inhibitors, such as procaine, Mg2+, ruthenium red, and spermine (Palade, 1987;McPherson and Campbell, 1993).. In our survey of natural ...

A major focus of the working group of Translational Cardiology are molecular mechanisms, which control muscle function and pathophysiological changes due to disease. We use a variety of techniques including biophysics, cell biology, molecular biology, high-resolution imaging (confocal and super resolution microscopy; voltage mapping), transgenic models and comprehensive phenotyping methods. In particular, calcium binding proteins and intracellular calcium signaling are a major interest. For example cardiac ryanodine receptor (RyR2) calcium release channels, which control cardiac contraction and relaxation and modulate physiological stress adaptation during the fight-or-flight response. On the other hand, RyR2 channel dysfunction contributes to heart failure, arrhythmias, and sudden cardiac death. We develop therapeutic options for RyR2 mutation carriers with the syndrome Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), characterized by stress-induced syncope and sudden death. ...

OBJECTIVE - : Sirolimus (SRL) is an immunosuppressant drug used to prevent rejection in organ transplantation and neointimal hyperplasia when delivered from drug-eluting stents. Major side effects of SRL include edema and local collection of intimal lipid deposits at drug-eluting stent sites, suggesting that SRL impairs endothelial barrier function (EBF). The aim of this study was to address the role of SRL on impaired EBF and the potential mechanisms involved. APPROACH AND RESULTS - : Cultured human aortic endothelial cells (HAECs) and intact human and mouse endothelium was examined to determine the effect of SRL, which binds FKBP12.6 to inhibit the mammalian target of rapamycin, on EBF. EBF, measured by transendothelial electrical resistance, was impaired in HAECs when treated with SRL or small interfering RNA for FKBP12.6 and reversed when pretreated with ryanodine, a stabilizer of ryanodine receptor 2 intracellular calcium release channels. Intracellular calcium increased in HAECs treated ...

According to our results in chickens, the possible channel units of DHPRs and RyRs in a sebokeratinocyte are peripherally located. This spatial relationship seems to resemble the arrangement of the smooth muscle cell in which the sarcoplasmic proteins, calsequestrin and RyRs colocalize with DHPRs in numerous, peripherally located sites within the caveolar domains (Moore et al., 2004; Pucovsky and Bolton, 2006). Due to the native arrangement of the stratified epidermis in our study, the exact array of DHPRs on the plasma membrane could not be revealed. However, RyRs were located in the proximity of the plasma membrane in horizontally aligned clusters, indicating the possible sites where the two channels might interact via spatial proximity. In a single smooth muscle cell of the urinary bladder, DHPRs have been shown to occupy the plasmalemma in longitudinal stripes that overlap almost entirely with the corresponding stripes formed by labelled RyR proteins (Moore et al., 2004). The authors ...

TY - JOUR. T1 - Ryanodine receptor S2808 phosphorylation in heart failure. T2 - Smoking gun or red herring. AU - Bers, Donald M. PY - 2012/3/16. Y1 - 2012/3/16. UR - http://www.scopus.com/inward/record.url?scp=84858652117&partnerID=8YFLogxK. UR - http://www.scopus.com/inward/citedby.url?scp=84858652117&partnerID=8YFLogxK. U2 - 10.1161/CIRCRESAHA.112.265579. DO - 10.1161/CIRCRESAHA.112.265579. M3 - Article. C2 - 22427320. AN - SCOPUS:84858652117. VL - 110. SP - 796. EP - 799. JO - Circulation Research. JF - Circulation Research. SN - 0009-7330. IS - 6. ER - ...

the ryanodine receptor (RyR) intracellular calcium release channel, are both required for normal muscle development and differentiation and for some calcium mobilization events in the ...

Experimental and mathematical modeling approaches identify a novel mechanism of heart failure, linking disrupted calcium homeostasis and impaired contractility of cardiacmyocytes to nanoscale reorganization of calcium release channels.

Suda, N.; Bodding, M.; Fleig, A.; Franzius, D.; Hoth, M.; Nishimura, S.; Imoto, K.; Takeshima, H.; Penner, R.: Slow calcium-induced calcium release (CICR) in Chinese hamster ovary (CHO) cells expressing skeletal ryanodine receptor (RyR) and chimaeric dihydropyridine receptor (DHPR). Biophysical Journal 70 (2), S. WPO49 - WPO49 (1996 ...

It is known that sarcoplasmic reticulum (SR) Ca2+ release in cardiac muscle is initiated via cardiac ryanodine receptor (RyR2) through a mechanism called Ca2+-induced Ca2+ release. However, how the SR Ca2+ release is terminated is undetermined. The objective of the current study is to understand the molecular basis and regulation of RyR2-mediated Ca2+ release termination and its role in the pathogenesis of cardiac diseases. Based on recent 3D structural analyses, the NH2-terminal region of RyR2 interacts with the channel domain via the central domain and undergoes dynamic conformational changes during channel gating. It has also been discovered that the NH2-terminal region consists of three distinct domains. HEK293 cell studies on domain deletions and disease mutations demonstrate that the different domains play different roles in RyR2 function. The NH2-terminal region is a major determinant of Ca2+ release activation and termination. Enhanced luminal Ca2+ activation of RyR2 has been linked to ...

In recent molecular cloning and expression studies, we have characterized mutations in the human muscle sodium channel that appear to underlie certain inherited myopathies. New studies being pursued in our group also address the questions of structure, receptor properties, and biophysical behavior of intracellular calcium release channels activated by inositol-1,4,5-triphosphate. These channels are expressed at extremely high levels ...in selected cells of the central nervous system, and may play a role in modulating neuronal excitability. view more. Research Areas: central nervous system, neuronal excitability, biophysiology, biochemistry, sodium channels, ion channels, molecular biology ...

The Janus protein, CLIC2. The 3-D structure of its water soluble form has been determined at 1.8 Å resolution (Cromer et al., 2007). CLIC2 interacts with the skeletal ryanodine receptor (RyR1) and modulates its channel activity (Meng et al., 2009 ...

Muscles. Dec. 19, 2014Webcast Cryo-Electron Microscopy: Decoding the 3D Structure of the Ryanodine Receptor Whenever muscles contract, so-called ryanodine receptors come into play. Calcium ions,

Principal Investigator：YAMAMOTO Takeshi, Project Period (FY)：2006 - 2007, Research Category：Grant-in-Aid for Scientific Research (C), Section：一般, Research Field：Circulatory organs internal medicine

Rabbit Polyclonal Anti-Ryanodine Receptor 2 Antibody. Validated: IHC, IHC-P. Tested Reactivity: Human, Mouse, Rat. 100% Guaranteed.

Consultation de terminologies scientifiques multilingues (définitions, traductions multilingues, synonymes, classifications, termes associés ou spécifiques ou génériques)

The table below shows the top 100 pain related interactions that have been reported for regulation of ryanodine-sensitive calcium-release channel activity. They are ordered first by their pain relevance and then by number of times they were reported for regulation of ryanodine-sensitive calcium-release channel activity. Please click on the INT link to display more detailed information on each interaction. ...

Chi X, Gong D, Ren K, Zhou G, Huang G, Lei J, et al. Molecular basis for allosteric regulation of the type 2 ryanodine receptor channel gating by key modulators. Proc Natl Acad Sci U S A. 2019 ;116(51):25575-25582. ...

Complete information for RYR3 gene (Protein Coding), Ryanodine Receptor 3, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium

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What is osteonecrosis? Your bones are made up of living cells that need a blood supply to stay healthy. In osteonecrosis, blood flow to part of a bone is reduced. This causes death of bone tissue, and the bone can eventually break down and the joint will collapse. Osteonecrosis can happen to any bone, but most often it develops in the ends of long bones, such as the: Thigh bone. Upper arm bone. Less often, the bones of the elbows, ankles, feet, wrists, and hands are affected. When the disease involves part of a bone in a joint, it ...

n-3 polyunsaturated fatty acids (PUFAs) can prevent life-threatening arrhythmias but the mechanisms responsible have not been established. There is strong evidence that part of the antiarrhythmic action of PUFAs is mediated through inhibition of the Ca(2+)-release mechanism of the sarcoplasmic reticulum (SR). It has also been shown that PUFAs activate protein kinase A (PKA) and produce effects in the cardiac cell similar to beta-adrenergic stimulation. We have investigated whether the inhibitory effect of PUFAs on the Ca(2+)-release mechanism is caused by direct inhibition of the SR Ca(2+)-release channel/ryanodine receptor (RyR) or requires activation of PKA. Experiments in intact cells under voltage-clamp show that the n-3 PUFA eicosapentaenoic acid (EPA) is able to reduce the frequency of spontaneous waves of Ca(2+)-release while increasing SR Ca(2+) content even when PKA activity is inhibited with H-89. This suggests that the EPA-induced inhibition of SR Ca(2+)-release is not dependent on activation

Comparative molecular field analysis (CoMFA) predicts that the large electrostatic field around the phosphate groups of ATP plays a crucial role in stabilizing the open state of the cardiac ryanodine receptor (RyR) channel. We therefore investigated the effects of adenosine-5-(beta,gamma-methylenetriphosphate) (AMP-PCP), an ATP analog with lower negative charge in this region, on the gating of the cardiac RyR channel. In the presence of 10 microM cytosolic Ca2+, AMP-PCP exhibited approximately 50% of the efficacy of ATP and optimal doses increased open probability (Po) to only 0.441 +/- 0.156 (n = 4), thus confirming the predictive ability of our preliminary CoMFA model. We also reveal that AMP-PCP has a higher affinity than ATP for the cardiac RyR, demonstrating that the structural properties required for tight binding to RyR differ from those necessary for recruiting long open states and high Po values. CoMFA identified very strong correlations between the structures of adenine-based ligands and

TY - JOUR. T1 - Nitric oxide-dependent activation of CaMKII increases diastolic sarcoplasmic reticulum calcium release in cardiac myocytes in response to adrenergic stimulation. AU - Curran, Jerry. AU - Tang, Lifei. AU - Roof, Steve R.. AU - Velmurugan, Sathya. AU - Millard, Ashley. AU - Shonts, Stephen. AU - Wang, Honglan. AU - Santiago, Demetrio. AU - Ahmad, Usama. AU - Perryman, Matthew. AU - Bers, Donald M. AU - Mohler, Peter J.. AU - Ziolo, Mark T.. AU - Shannon, Thomas R.. PY - 2014/2/3. Y1 - 2014/2/3. N2 - Spontaneous calcium waves in cardiac myocytes are caused by diastolic sarcoplasmic reticulum release (SR Ca2+ leak) through ryanodine receptors. Beta-adrenergic (β-AR) tone is known to increase this leak through the activation of Ca-calmodulin-dependent protein kinase (CaMKII) and the subsequent phosphorylation of the ryanodine receptor. When b-AR drive is chronic, as observed in heart failure, this CaMKII-dependent effect is exaggerated and becomes potentially arrhythmogenic. Recent ...

Objectives:Sepsis is associated with cardiac contractile dysfunction attributed to alterations in Ca2+ handling. We examined the subcellular mechanisms involved in sarcoplasmic reticulum Ca2+ loss that mediate altered Ca2+ handling and contractile dysfunction associated with sepsis.Design:Randomized

Background: Recent genetic studies identified mutations in CALM1 or CALM2, 2 of the 3 human genes encoding calmodulin (CaM), in both catecholaminergic polymorphic ventricular tachycardia (CPVT) and long QT syndrome (LQTS). CPVT is commonly caused by mutations in sarcoplasmic reticulum genes that increase diastolic Ca leakage through ryanodine receptor (RyR2) Ca relase channels, whereas LQTS is usually caused by dysfunctional plasma membrane ion channels. How mutant CaM causes either CPVT or LQTS is unknown.. Objective: To gain mechanistic insight into how CaM mutations cause divergent human arrhythmia phenotypes.. Methods and Results: We prepared recombinant wild-type (WT) and mutant CaM proteins associated with either CPVT (N54I, N98S) or LQTS ( F142L, D130G). LQTS CaM mutations drastically reduce Ca binding affinity to CaM, whereas CPVT mutations have either no effect (N54I) or slightly reduce Ca binding affinity (N98S). At physiological free CaM [100 nM] and Ca [120 nM], CPVT CaMs ...

In the present report, we provide evidence for the expression of all 3 isoforms of the SR Ca2+-release channel in the human heart. During heart failure, specific changes in isoform expression were found with increased expression of isoform 1 of the SR Ca2+-release channel in human failing cardiomyocytes. Coexpression of the different isoforms of the SR Ca2+-release channel in human cardiomyocytes is a novel finding; however, different investigators have described this phenomenon in various animal species and different organs, particularly in the brain.16 17 In the heart, coexpression of the SR Ca2+-release channel isoform 1 and isoform 2 by PCR methods was reported in mouse cardiac tissue,9 and expression of isoforms 2 and 3 has been determined in porcine cardiac tissue.10 Moreover, in our laboratory, all 3 isoforms of the SR Ca2+-release channel were discovered on the mRNA and protein levels in different myocardial chambers of the nonfailing heart.12 The detection of isoform 1 in the human ...

Ca(2+) sparks are highly localized Ca(2+) transients caused by Ca(2+) release from sarcoplasmic reticulum through ryanodine receptors (RyR). In smooth muscle, Ca(2+) sparks activate nearby large-conductance, Ca(2+)-sensitive K(+) (BK) channels to generate spontaneous transient outward currents (STOC). The properties of individual sites that give rise to Ca(2+) sparks have not been examined systematically. We have characterized individual sites in amphibian gastric smooth muscle cells with simultaneous high-speed imaging of Ca(2+) sparks using wide-field digital microscopy and patch-clamp recording of STOC in whole cell mode. We used a signal mass approach to measure the total Ca(2+) released at a site and to estimate the Ca(2+) current flowing through RyR [I(Ca(spark))]. The variance between spark sites was significantly greater than the intrasite variance for the following parameters: Ca(2+) signal mass, I(Ca(spark)), STOC amplitude, and 5-ms isochronic STOC amplitude. Sites that failed to generate

Ligation of the T-cell receptor/CD3 complex results in global Ca(2+) signals that are essential for T-cell activation. We have recently reported that these global Ca(2+) signals are preceded by localized pacemaker Ca(2+) signals. Here, we demonstrate for the first time for human T cells that an increase in signal frequency of subcellular pacemaker Ca(2+) signals at sites close to the plasma membrane, in the cytosol and in the nucleus depends on the type 3 ryanodine receptor (RyR) and its modulation by cyclic ADP-ribose. The spatial distribution of D-myo-inositol 1,4,5-trisphosphate receptors and RyRs indicates a concerted action of both of these receptors/Ca(2+) channels in the generation of initial pacemaker signals localized close to the plasma membrane. Inhibition or knockdown of RyRs resulted in significant decreases in (1) the frequency of initial pacemaker signals localized close to the plasma membrane, and (2) the frequency of localized pacemaker Ca(2+) signals in the inner cytosol. Moreover,

As mentioned above, RyRs are often complexed with several accessory proteins, forming an intricate multi-protein array [32, 33]. The best known RyR-interacting proteins are CaM, which tonically inhibits RyR2 activity and produces biphasic effects on RyR1 [34, 35]; FKBP12 and FKBP12.6, which stabilize RyR1 and RyR2 closures [36-38]; and the ternary complex triadin-junctin-calsequestrin, which senses luminal Ca2+ content and modulates RyR activity by acting either as a Ca2+ reservoir or as a direct channel ligand [39-47]. More recently, RyR2 has been found to hold anchoring sites for protein kinase (PK)A, protein phosphatase (PP)1, the cAMP-specific phosphodiesterase (PDE)4D3 and Ca2+/calmodulin-dependent protein kinase (CaMK)II [37, 48], emphasizing the importance of RyR2 regulation by phosphorylation [32]. In cardiac cells, sorcin exerts protein-protein interactions with the RyR and inhibits Ca2+ release in a Ca2+-dependent manner [49, 50].. The binding sites of several regulatory proteins ...

We showed that CSQ2-associated RyR2 channels, activated by 1 μM cytosolic Ca2+, were sensitive to luminal Ca2+. They were not sensitive to changes in luminal Mg2+. Thus, the CSQ2-dependent luminal RyR2 Ca2+ regulation mechanism distinguishes between these ions. It does not require the presence of another cytosolic activator (ATP or sulmazole). It does not require the presence of additional free CSQ2 in the luminal bath as illustrated by Fig. 1 B (filled circles) where regulation occurs with no unbound CSQ2 in the lumenal bath. This means CSQ2-dependent regulation does not involve CSQ2 association/dissociation and that made it impractical to define the CSQ2 dose dependency. We considered examining the dose dependency of CSQ2 reassociation over a set interval but the physiological importance of this parameter is not entirely clear. Instead, we simply elected to define function at a set bath CSQ2 concentration, a concentration like that used successfully by other groups (Gyorke et al., 2004; Beard ...

Activation of Ca2+-sensitive, large-conductance potassium (BK) channels in vascular smooth muscle cells (VSMCs) by local, ryanodine receptor-mediated Ca2+ signals (Ca2+ sparks) acts as a brake on pressure-induced (myogenic) vasoconstriction-a fundamental mechanism that regulates blood flow in small resistance arteries. We report that physiological intraluminal pressure within resistance arteries activated cGMP-dependent protein kinase (PKG) in VSMCs through oxidant-induced formation of an intermolecular disulfide bond between cysteine residues. Oxidant-activated PKG was required to trigger Ca2+ sparks, BK channel activity, and vasodilation in response to pressure. VSMCs from arteries from mice expressing a form of PKG that could not be activated by oxidants showed reduced Ca2+ spark frequency, and arterial preparations from these mice had decreased pressure-induced activation of BK channels. Thus, the absence of oxidative activation of PKG disabled the BK channel-mediated negative feedback ...

Our study presents the first demonstration of dantrolene inhibition of mammalian RyR1 and RyR2 from recordings of single RyR and permeabilized cardiomyocytes. The finding that a physiologic concentration of CaM is required for dantrolene inhibition of these RyRs provides an answer to the long-standing question of why dantrolene, an inhibitor of SR Ca2+ release, had no effect on the activity of mammalian RyR1 and RyR2 in previous single channel studies (Szentesi et al., 2001; Diaz-Sylvester et al., 2008; Wagner et al., 2014). Because CaM readily dissociates from the RyR complex (Guo et al., 2011), CaM would have been absent during those experiments. IC50 for CaM facilitation of dantrolene inhibition appears to be ∼10 nM for wt-CaM (Fig. 1E) and 5.9 nM for N98S-CaM (Fig. 4C). These values are ∼2-fold lower than the binding affinities for these CaMs on RyR2 (Guo et al., 2011; Hwang et al., 2014).. [3H]ryanodine binding assays have demonstrated a reduction of CaM activation of purified pig RyR1 ...

Cardiac ryanodine receptors (RyR2s) are Ca2+ release channels clustering in the sarcoplasmic reticulum membrane. These clusters are believed to be the elementary units of Ca2+ release. The distribution of these Ca2+ release units plays a critical role in determining the spatio-temporal profile and stability of sarcoplasmic reticulum Ca2+ release. RyR2 clusters located in the interior of cardiomyocytes are arranged in highly ordered arrays. However, little is known about the distribution and function of RyR2 clusters in the periphery of cardiomyocytes. Here, we used a knock-in mouse model expressing a green fluorescence protein (GFP)-tagged RyR2 to localize RyR2 clusters in live ventricular myocytes by virtue of their GFP fluorescence. Confocal imaging and total internal reflection fluorescence microscopy was employed to determine and compare the distribution of GFP-RyR2 in the interior and periphery of isolated live ventricular myocytes and in intact hearts. We found tightly ordered arrays of ...

45Ca2+release assays were performed using 4-Cm C, after lymphocytes had been actively loaded for 1 h, with radioactive 45Ca2+. Cells were washed as above. Supernatant (200 μl) from the final wash was reserved for scintillation counting as prestimulated released 45Ca2+. Cell pellets were resuspended in 1 ml calcium-depleted HBSS buffer, and 200-μl aliquots of approximately 0.8 × 106viable cells were transferred to separate microcentrifuge tubes and incubated with increasing concentrations of 4-Cm C. Each sample was briefly centrifuged, and the resulting supernatant was collected and radioactivity determined by liquid scintillation counting. Counts per minute obtained for prestimulation were subtracted from those obtained after stimulation of cells with 4-Cm C. The concentration of 4-Cm C causing half-maximal release (EC50) of 45Ca2+was determined by curve fitting. Parallel experiments were performed where thapsigargin14 was used to establish a reference standard for complete release of ...

is a human gene associated with the release of Calcium ions from the sarcoplasmic reticulum triggering muscular contraction through calcium-induced calcium release ... It is a transmembrane protein on the sarcoplasmic reticulum due to a well defined hydrophobic section, and it forms a quaternary complex with Ryanodine receptors (RyR ... The luminal (inner compartment of the sarcoplasmic reticulum) section of Triadin has areas of highly charged amino acid residues that act as luminal Ca2+ receptors ...

Vlutations in either type 1 ryanodine receptor (RyR1) or the dihydropyridine receptor subunit Cav1.1 cause malignant hyperthermia susceptibility (MHS) in humans...

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Skeletal muscle excitation-contraction (EC) coupling depends upon interactions at triad junctions between L- type Ca2+ channels (dihydropyridine receptors, DHPR...

Takano, K, Liu, D, Tarpey, P et al 2012, An X-linked Channelopathy with Cardiomegaly due to a CLIC2 Mutation Enhancing Ryanodine Receptor Channel Activity, Human Molecular Genetics, vol. 21, no. 20, pp. 4497-4507. ...

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Ca2+ can influence various cellular outcomes by either entering the cell from the extracellular milieu or by being released from intracellular stores, such as the endoplasmic reticulum (ER). Ca2+ release from the ER is influenced by a number of factors like the activation of G-protein coupled receptors and receptor tyrosine kinases which activate downstream pathways leading to Ca2+ release. There are also membrane proteins located on the ER membrane which are known to influence Ca2+ release. Such proteins include IP3R, ryanodine receptors (RyRs) and various pumps. Many compounds can either promote or inhibit Ca2+ release from the ER. Alomone Labs is pleased to offer various small molecules and peptides known to modulate Ca2+ release from intracellular stores.. ...

Luminal Ca2+ regulation of RyR2 channels by the CSQ2-R33Q and CSQ2-L167H mutants. Mutant CSQ2 (0.5 μg/ml) was added to the luminal side of previously CSQ2-stri

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3) Ca2+ channels in SR membrane situated directly opposite t-tubules are Ca2+ release channels (the RYRs). The RYRs and SHPRs are coupled together and physically link the t tubules and SR ...

mpiexec -hosts bwlf01,bwlf02,bwlf03 -n 2 ./fib -numProcs=3 -scheds=2 -d1 v2 45 30 +RTS -N2 : -n 1 ./fib -numProcs=3 -scheds=4 -d1 v2 45 30 +RTS -N4 137.195.143.101:21394:0 #SPARK=1114 max_SPARK=183 max_THREAD=[3,1,1] 137.195.143.101:21394:0 #FISH_sent=3 #SCHED_rcvd=1 137.195.143.103:22027:0 #SPARK=261 max_SPARK=2 max_THREAD=[0,1,1,1,1] 137.195.143.103:22027:0 #FISH_sent=209 #SCHED_rcvd=208 137.195.143.102:22374:0 #SPARK=221 max_SPARK=3 max_THREAD=[1,1,1] 137.195.143.102:22374:0 #FISH_sent=173 #SCHED_rcvd=172 {v2, seqThreshold=30, parThreshold=30} fib 45 = 1836311903 {runtime=10.502205s ...

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Demonstrating how putting the colours together gives us the full picture. This resource was developed by The Solar Spark at the University of Edinburgh.

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I meant to positively rep you. I dont know what happened, because I didnt change the button, and I wasnt using my phone, where its easy to fumble because everythings so small. Im so sorry -- I though your post was right on target. As soon as I can rep you again, I will ...

SMACK-288] - The parsing of the result for a LeafNode.getItems() call is incorrect. It creates a DefaultPacketExtension instead of an Item for every other item in the result ...