Activation of a calmodulin (CaM)-dependent protein kinase associated with rabbit skeletal-muscle sarcoplasmic reticulum (SR) results in the phosphorylation of polypeptides of 450, 360, 165, 105, 89, 60, 34 and 20 kDa. Radioligand-binding studies indicated that a membrane-bound 60 kDa polypeptide contained both CaM- and ATP-binding domains. Under renaturing conditions on nitrocellulose blots, the 60 kDa polypeptide of the membrane exhibited CaM-dependent autophosphorylation activity, suggesting that it was the CaM-dependent protein kinase of SR. Ca2+/CaM-independent autophosphorylation of polypeptides of 62 and 45 kDa was found to occur in the light SR, whereas the Ca2+/CaM-dependent autophosphorylation activity was enriched in the heavy SR. Both these kinase activities were absent from transverse tubules, although these membranes were enriched in CaM-binding polypeptides of 160, 100 and 80 kDa. In the absence of Ca2+, CaM bound to a 33 kDa polypeptide of the membrane. The purified ryanodine ...

Single ventricular myocytes were isolated by collagenase digestion from the hearts of 6-8-month-old male Wistar rats in either the control (euthyroid) state or after 7 days of daily injection of 0.64 mg/kg thyroxine (hyperthyroid). Myocytes were field-stimulated from slack length, and contraction was measured with an inverted microscope-photodiode array-computer apparatus. The effect of pacing rate and ouabain administration on systolic and diastolic function was examined. Single myocytes isolated from hyperthyroid hearts maintain the properties of bulk muscle, because maximal twitch velocity is augmented 98% and the time course of contraction as measured by the time to peak shortening, relaxation time, or contraction duration is abbreviated 39%. Spontaneous sarcoplasmic reticulum calcium release, as measured by the occurrence of contractile waves, is increased in the hyperthyroid myocytes. This increased frequency of spontaneous sarcoplasmic reticulum calcium release is most marked under ...

Protein kinase C regulates the activity of a diverse group of cellular proteins including membrane ion channel proteins. Although protein kinase C and its substrate protein have been identified in both membrane and cytosolic fractions in the heart, the physiological role of this kinase in the regulation of cardiac function remains unknown. We examined the physiological role of protein kinase C by stimulating its activity with 12-deoxyphorbol 13 isobutyrate 20 acetate (DPBA) in human trabeculae carneae. This resulted in decreased peak isometric twitch force and peak intracellular sarcoplasmic reticulum calcium release as detected with aequorin. Furthermore, in the presence of DPBA, steady-state force-[Ca2+] relations were shifted to higher intracellular calcium concentrations, and the Hill coefficient was reduced, indicating a decrease in responsiveness of the myofilaments to calcium and a change in cooperativity among thin filament proteins, respectively. Thus, DPBA affects not only ...

A compelling mystery in the study of exercise is mechanisms of skeletal muscle fatigue. Broadly described, muscle fatigue is the uncomfortable sensation that particular muscle groups are shutting down and muscle force production cannot continue. More specifically, muscle fatigue is defined as an activity-induced inability to continue to produce a desired level of force. Several groups suggest that a major cause of force loss during fatigue is reductions in the rates of sarcoplasmic reticulum (SR) calcium (Ca2+) release and uptake. These changes result in diminished contractile machinery activation, reduced force production and slowed relaxation. During exercise, adenosine 5-triphosphate (ATP) is the energy currency that is used to support force production. As a result of ATP hydrolysis and re-synthesis, adenosine diphosphate (ADP) and adenosine monophosphate (AMP) levels rise. AMP kinase (AMPK) is an enzyme that becomes activated as a result of increased AMP levels. It is thought to function as ...

TY - JOUR. T1 - Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia. AU - Knollmann, Björn C.. AU - Chopra, Nagesh. AU - Hlaing, Thinn. AU - Akin, Brandy. AU - Yang, Tao. AU - Ettensohn, Kristen. AU - Knollmann, Barbara E.C.. AU - Horton, Kenneth D.. AU - Weissman, Neil J.. AU - Holinstat, Izabela. AU - Zhang, Wei. AU - Roden, Dan M.. AU - Jones, Larry R.. AU - Franzini-Armstrong, Clara. AU - Pfeifer, Karl. PY - 2006/9/1. Y1 - 2006/9/1. N2 - Cardiac calsequestrin (Casq2) is thought to be the key sarcoplasmic reticulum (SR) Ca2+ storage protein essential for SR Ca2+ release in mammalian heart. Human CASQ2 mutations are associated with catecholaminergic ventricular tachycardia. However, homozygous mutation carriers presumably lacking functional Casq2 display surprisingly normal cardiac contractility. Here we show that Casq2-null mice are viable and display normal SR Ca2+ release and contractile function ...

Ion pumps are integral membrane proteins responsible for transporting ions against concentration gradients across biological membranes. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), a member of the P-type ATPases family, transports two calcium ions per hydrolyzed ATP molecule via an alternating-access mechanism. High-resolution crystallographic structures provide invaluable insight on the structural mechanism of the ion pumping process. However, to understand the molecular details of how ATP hydrolysis is coupled to calcium transport, it is necessary to gain knowledge about the conformational transition pathways connecting the crystallographically resolved conformations. Large-scale transitions in SERCA occur at time-scales beyond the current reach of unbiased molecular dynamics simulations. Here, we overcome this challenge by employing the string method, which represents a transition pathway as a chainofstates linking two conformational endpoints. Using a multiscale methodology, we have ...

In muscle cells, the excitation-contraction cycle is triggered by an increase in the concentration of free cytoplasmic Ca(2+). The Ca(2+)-ATPase present in the membrane of the sarcoplasmic reticulum (SR) pumps Ca(2+) from the cytosol into this intracellular compartment, thus promoting muscle relaxation. The microsomal fraction derived from the longitudinal smooth muscle of the body wall from the sea cucumber Ludwigothurea grisea retains a membrane-bound Ca(2+)-ATPase that is able to transport Ca(2+) mediated by ATP hydrolysis. Immunological analyses reveal that monoclonal antibodies against sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA1 and SERCA2a) cross-react with a 110 kDa band, indicating that the sea cucumber Ca(2+)-ATPase is a SERCA-type ATPase. Like the mammalian Ca(2+)-ATPase isoforms so far described, the enzyme also shows a high affinity for Ca(2+) and ATP, has an optimum pH of approximately 7.0 and is sensitive to thapsigargin and cyclopiazonic acid, specific inhibitors of the ...

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 ...

The sarco(endo)plasmic reticulum calcium ATPase (SERCA) family of proteins function as calcium pumps in the endoplasmic reticulum (ER) and sarcoplasmic reticulum (SR) membranes. SERCA1a is found exclusively in fast-twitch muscle cells and mediates muscle relaxation by pumping calcium back into the SR after calcium has been released into the cytoplasm to elicit muscle contraction. The mechanism which allows SR biogenesis is not known, but SR membrane is believed to bud from the ER. One hypothesis is that SERCA1a proteins play a significant role in SR biogenesis in fast-twitch skeletal muscle due the proteins large size and clustering into large arrays in the SR membrane. SERCA1a arrays could recruit lipids which would allow for a large increase in membrane size that could result in the formation of the SR. Also, SERCA1a is highly expressed during the early stages of myogenesis, at the same time the first emergence of the SR is observed. It is known that SERCA1a contains ER targeting information ...

Triadin, also known as TRDN, is a human gene associated with the release of Calcium ions from the sarcoplasmic reticulum triggering muscular contraction through calcium-induced calcium release. Triadin is a multiprotein family, arising from different processing of the TRDN gene on chromosome 6. It is a transmembrane protein on the sarcoplasmic reticulum due to a well defined hydrophobic section and it forms a quaternary complex with the cardiac Ryanodine receptor (RYR2), calsequestrin (CASQ2) and junctin proteins. 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. Triadin is also able to sense luminal Ca2+ concentrations by mediating interactions between RYR2 and CASQ2. Triadin has several different forms; Trisk 95 and Trisk 51, which are expressed in skeletal muscle, and Trisk 32 (CT1), which is mainly expressed in cardiac muscle. TRDN has been shown to interact with RYR1. Triadin ...

TY - JOUR. T1 - The role of sarcolipin and ATP in the transport of phosphate ion into the sarcoplasmic reticulum. AU - Becucci, Lucia. AU - Guidelli, Rolando. AU - Karim, Christine B.. AU - Thomas, David D.. AU - Veglia, Gianluigi. N1 - Funding Information: This work was supported by grants from Ente Cassa di Risparmio di Firenze (R.G.), the Italian Ministero dellIstruzione, dellUniversità e della Ricerca (R.G.), and the National Institutes of Health (grants GM64742, HL80081, and GM072701 to G.V). PY - 2009/11/15. Y1 - 2009/11/15. N2 - In a previous study, sarcolipin (SLN) was shown to form channels selective toward chloride ion when incorporated in a mercury-supported tethered bilayer lipid membrane (tBLM). Its incorporation had only a modest permeabilizing effect on phosphate ion. In this note the resistance of a tBLM membrane incorporating sarcolipin was investigated by electrochemical impedance spectroscopy in aqueous solutions of 0.05 M sodium phosphate of pH ranging from 5.3 to 8, in ...

TY - JOUR. T1 - Transmembrane Ca2+ gradient-mediated change of fluidity in the inner layer of phospholipids modulates Ca2+-ATPase of sarcoplasmic reticulum. AU - Tu, Yaping. AU - Xu, H.. AU - Yang, F. Y.. PY - 1994. Y1 - 1994. N2 - Sarcoplasmic reticulum (SR) vesicles with (1000 folds) or without transmembrane Ca2+ gradient have been prepared. Different fluorescence probes (DPH, TMA-DPH and n-AS), were used to determine the effect of transmembrane Ca2+ gradient on the lipid fluidity both in outer and inner layer of Ca2+-ATPase-containing SR vesicles. The results showed that transmembrane Ca2+ gradient could significantly decrease the fluidity of the inner layer of SR membrane, while no obvious change was monitored in the outer layer. This may be deduced that Ca2+-ATPase might be modulated mainly by the transmembrane Ca2+ gradient-mediated alteration of physical state of phospholipid in the inner layer of SR membrane.. AB - Sarcoplasmic reticulum (SR) vesicles with (1000 folds) or without ...

The precise control of Ca2+ levels during the contraction-relaxation cycle in cardiac myocytes is extremely important for normal beat-to-beat contractile activity. The sarcoplasmic reticulum (SR) plays a key role controlling calcium concentration in the cytosol. The SR Ca2+-ATPase (SERCA2) transports Ca2+ inside the SR lumen during relaxation of the cardiac myocyte. Calsequestrin (Casq2) is the main protein in the SR lumen, functioning as a Ca2+ buffer and participating in Ca2+ release by interacting with the ryanodine receptor 2 (RyR2) Ca2+-release channel. Alterations in normal Ca2+ handling significantly contribute to the contractile dysfunction observed in cardiac hypertrophy and in heart failure. Transcriptional regulation of the SERCA2 gene has been extensively studied and some of the mechanisms regulating its expression have been elucidated. Overexpression of Sp1 factor in cardiac hypertrophy downregulates SERCA2 gene expression and increased levels of thyroid hormone up-regulates its ...

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 ...

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TY - JOUR. T1 - Synergistic dual automaticity in sinoatrial node cell and tissue models. AU - Zhang, Hong. AU - Joung, Boyoung. AU - Shinohara, Tetsuji. AU - Mei, Xi. AU - Chen, Peng-Sheng. AU - Lin, Shien-Fong. PY - 2010. Y1 - 2010. N2 - Background: The mechanism of sinoatrial node (SAN) automaticity is traditionally attributed to membrane ion currents. Recent evidence indicates spontaneous sarcoplasmic reticulum (SR) Ca2+ cycling also plays an important role. Methods and Results: A computer simulation on SAN cell and 1D tissue model was performed. In the SAN cells, SR Ca2+ cycling broadly modulated the sinus rate from 1.74 Hz to 3.87 Hz. Shortening of the junctional SR refilling time and increase of SR Ca2+ release were responsible for sinus rate acceleration. However, under the fast SR Ca2+ cycling, decreased L-type Ca2+ current (ICaL) resulted in irregular firing. When Ca2+ cycling was suppressed, If and ICaT both acted to stabilize the pacemaker rhythm, but ICaT had less effect than If. At ...

Intracellular calcium recycling plays a critical role in regulation of systolic and diastolic function in cardiomyocytes. Here, we...

TY - JOUR. T1 - Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. AU - Gómez, A. M.. AU - Valdivia, H. H.. AU - Cheng, H.. AU - Lederer, Miriam R.. AU - Santana, Luis Fernando. AU - Cannell, M. B.. AU - McCune, S. A.. AU - Altschuld, R. A.. AU - Lederer, W. J.. PY - 1997/5/2. Y1 - 1997/5/2. N2 - Cardiac hypertrophy and heart failure caused by high blood pressure were studied in single myocytes from hypertensive rats (Dahl SS/Jr) and SH-HF rats in heart failure. Confocal microscopy and patch-clamp methods were used to examine excitation-contraction (EC) coupling, and the relation between the plasma membrane calcium current I(Ca) and evoked calcium release from the sarcoplasmic reticulum (SR), which was visualized as calcium sparks. The ability of I(Ca) to trigger calcium release from the SR in both hypertrophied and failing hearts was reduced. Because i(Ca) density and SR calcium-release channels were normal, the defect appears to reside in a ...

Contraction of the heart is a complex process initiated by the electrical excitation of cardiac myocytes (excitation-contraction coupling, ECC). In cardiac myocytes, Ca2+ influx induced by activation of voltage-dependent L-type Ca channels (DHP receptors) upon membrane depolarization triggers the release of Ca2+ via Ca2+ release channels (ryanodine receptors) of sarcoplasmic reticulum (SR) through a Ca2+ -induced Ca release (CICR) mechanism. Ca2+ ions released via the CICR mechanism diffuse through the cytosolic space to contractile proteins to bind to troponinC resulting in the release of inhibition induced by troponinI. The Ca2+ binding to troponinC thereby triggers the sliding of thin and thick filaments, that is, the activation of a crossbridge and subsequent cardiac force development and/or cell shortening. Recovery occurs as Ca2+ is pumped out of the cell by the Na+/Ca2+ exchanger (NCX) or is returned to the sarcoplasmic reticulum (SR) by sarco(endo)plasmic Ca2+ -ATPase (SERCA) pumps on ...

Backgrounds Previous studies showed that overexpression of sarco-endoplasmic reticulum calcium ATPase (SERCA2a) in a variety of heart failure (HF) models was associated with greatly enhanced cardiac performance. However, it still undefined the effect of SERCA2a overexpression on the systemic inflammatory response and neuro-hormonal factors. Methods A rapid right ventricular pacing model of experimental HF was used in beagles. Then the animals underwent recombinant adeno-associated virus 1 (rAAV1) mediated gene trans¬fection by direct intra-myocardium injection. HF animals were randomized to receive the SERCA2a gene, enhanced green fluorescent protein (control) gene, or equivalent phosphate buffered saline. Thirty days after gene delivery, the cardiac function was evaluated by echocardiographic testing. The protein level of SERCA2a was measured by western blotting. The proteomic analysis of left ventricular (LV) sample was determined using two-dimensional (2-D) gel electrophoresis and MALDI-TOF-MS. The

The steady-state ATPase activity of sarcoplasmic-reticulum (Ca(2+)-Mg2+)-ATPase is inhibited by thapsigargin at a molar ratio of 1:1, with a dissociation constant for thapsigargin estimated to be in the sub-nanomolar range. In the presence of thapsigargin, only a single Ca2+ ion binds to the ATPase. Similarly, addition of thapsigargin to the ATPase incubated in the presence of Ca2+ results in the release of one of the two originally bound Ca2+ ions. As monitored by the fluorescence of nitrobenzo-2-oxa-1,3-diazole-labelled ATPase, thapsigargin appears to shift the transition between E1 and E2 conformations towards E2. Addition of thapsigargin prevents phosphorylation of the ATPase by P(i) and results in a very low steady-state level of phosphorylation of the ATPase by ATP, as observed previously for nonylphenol. ...

Areas of active investigation include: use of laser-scanning confocal microscopy to measure calcium sparks, which are brief localized increases in fluorescence from a Ca-indicator such as fluo-3 that are thought to be reflective of the transient opening of one or a few RyRs (=ryanodine receptors), the Ca release channels of the sarcoplasmic reticulum (SR); the possibility that the mechanism of activation of RyRs involves both voltage-gating and Ca-gating; the nature of the mechanism whereby SR Ca release is inactivated by a rise in myoplasmic free [Ca]; the possibility that either activation or inactivation of SR Ca release may vary with the RyR isoform composition (RyR1, RyR3, etc.); estimation of local Ca movements within the sarcomere by means of computer modeling, including estimation of the kinetics of binding of Ca to the intracellular Ca buffers troponin, parvalbumin, ATP, and the SR Ca pump ...

Catalyzes the formation of the signaling molecule cAMP downstream of G protein-coupled receptors (PubMed:17916776, PubMed:17110384). Functions in signaling cascades downstream of beta-adrenergic receptors in the heart and in vascular smooth muscle cells (PubMed:17916776). Functions in signaling cascades downstream of the vasopressin receptor in the kidney and has a role in renal water reabsorption. Functions in signaling cascades downstream of PTH1R and plays a role in regulating renal phosphate excretion. Functions in signaling cascades downstream of the VIP and SCT receptors in pancreas and contributes to the regulation of pancreatic amylase and fluid secretion (By similarity). Signaling mediates cAMP-dependent activation of protein kinase PKA. This promotes increased phosphorylation of various proteins, including AKT. Plays a role in regulating cardiac sarcoplasmic reticulum Ca(2+) uptake and storage, and is required for normal heart ventricular contractibility. May contribute to normal heart ...

These results show that vasostatin, an NH2-terminal fragment of human calreticulin, can inhibit endothelial cell proliferation in vitro, suppress neovascularization in vivo, and prevent or reduce growth of experimental tumors. Calreticulin, a ubiquitous and highly conserved protein originally identified in skeletal muscle sarcoplasmic reticulum, serves as one of the major storage depots for calcium ions within the endoplasmic reticulum and participates in calcium signaling ((34)-(36)). The NH2-domain of calreticulin, which includes aa 1-180, is the most conserved domain among the calreticulins so far cloned and has no homology to other protein sequences ((34), (35)). Although it does not bind calcium, it can bind the cytoplasmic domain of α subunits of integrins regulating cell attachment ((37)), can interact with the nuclear receptors for glucocorticoid, androgen, and retinoic acid, regulating their binding to DNA ((38)), and can, once phosphorylated, bind stem-loop structures at the 3′-end ...

Muscle Contraction When a action potential arrives via a motor neurone to the muscle - it depolarizes the transverse tubules, which triggers calcium to be released from the sarcoplasmic reticulum by the opening of calcium channels in the sarcoplasmic reticulum membrane.. The calcium ions bind with the troponin molecules on the actin filaments - causing them to change shape, this causes the tropomyosin to move, exposing a site that the myosin can bind to.. The myosin then quickly tilts through 45 degrees - so the actin gets pulled towards the centre of the sacromere. As teh head tilts the ADP and Pi are released, and an ATP molecule takes their place.. The myosin head then hydrolyses the ATP to ADP and Pi - the energy generated from this is used to detach the myosin head from the actin filament. The cycle then starts all over again!. ...

Recent studies have been directed towards the potential therapeutic value of improving the sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA) function in the failing myocardium. Overexpression of SERCA pump or inhibiting the function of phospholamban (PLB) has been shown to improve the cardiac function in failing myocardium. Towards this goal, we enhanced the SERCA pump activity in both atria and ventricle by ablating its key regulators, PLB and sarcolipin (SLN). The homozygous double knockout (dKO) pups were delivered in Mendelian ratio and reached adulthood without any visible abnormalities. However, these mice develop cardiac hypertrophy. The heart weight to body weight ratio significantly increased in 3- 4 months old dKO mice (WT-3.08±0.11 vs. dKO-4.14±0.14) and is associated with enlargement of myocytes (WT-117±8 μm2 vs. dKO-166±10 μm2). Ablation of PLB and SLN did not affect the expression of major Ca2+ handling proteins including SERCA2a, calsequestrin, L-type Ca2+ channel and ...

The mutation underlying myotonic dystrophy is the expansion of polymorphic CTG repeat in the 3-noncoding region of the myotonin protein kinase (MtPK) gene mapping to chromosome 19q13.3. A full-length cDNA of human MtPK was cloned and expressed in COS-1 cells. We purified native full-length MtPK from rat skeletal muscle. This 70 kDa MtPK is localized in sarcoplasmic reticulum fraction, whereas the previously reported 55 kDa protein was observed in nuclear extract or the sarcoplasmic reticulum membrane. Based on the cDNA sequence, human MtPK was previously reported to have two amino acid sequence variations at the C-terminus, one GAARAP (RAP type) and PALPEP (PEP type). The MtPK purified appeared to be almost entirely RAP type. Stable expression of MtPK in mouse C2C12 cells caused the activation of chloride efflux. Expansion of CTG repeats suppressed myogenic differentiation. Collectively, the results indicate that prolonged MtPK activation provides a link between intracellular signal transduction

Calcium pumps transport calcium back into sarcoplasmic reticulum, ending an action potential and causing relaxation. The process of muscle contraction will continue until the action potential is terminated. Relaxation is achieved when calcium pumps have actively transported calcium back into the sarcoplasmic reticulum, reversing the changes that previously occurred in troponin. Tropomyosin is now back in its original position covering the myosin binding sites on actin, preventing crossbridges and power stroke cycling. - Stock Video Clip K005/0663

The endoplasmic reticulum is a major organelle in all eukaryotic cells which performs multiple functions including protein and lipid synthesis and sorting, drug metabolism, and Ca 2+ storage and release. The endoplasmic reticulum, and its specialized muscle counterpart the sarcoplasmic reticulum, is the largest and most extensive of Ca 2+ storage organelle in eukaryotic cells, often occupying in excess of 10% of the cell volume. There are three major components of Ca 2+ storage organelles which mediate their major functions: Ca 2+ uptake, mediated by pumps and exchangers; storage enhanced by luminal Ca 2+ binding proteins, and Ca 2+ mobilization mediated by specific ion channels. Ca 2+ mobilization from the endoplasmic reticulum plays a central role in Ca 2+ signaling. Through Ca 2+ release channels in its membrane, the pervading and plastic structure of the endoplasmic reticulum allows Ca 2+ release to be rapidly targeted to specific cytoplasmic sites across the whole cell. That several

Author: P. SATHYAVATHI. Category: Physiology. [Download PDF]. Abstract:. Background and objectives: Calcium is the prime mediator of the contractile mechanism in frog ventricle. Sarcoplasmic reticulum (SR) releases calcium by a well-known calcium induced calcium release (CICR) mechanism. CICR is mediated by ryanodine receptor (RyR) and inositol 1,4, 5- triphosphate (IP3) receptors on the SR membrane. This increase in cytosolic calcium concentration causes contraction of the cardiac muscle. Aim :The study aims at examining the interdependent role of the known calcium release channels on the SR in frog ventricle. Materials and Methods and the Study Design: Isolated ventricular strips of frogs (rana hexadactyla) were used for the study. The study design includes subjecting the ventricular strip to continuous electrical stimulation with imposed rest periods intermittently to examine the diastolic depletion of calcium from the SR. The magnitude of decay of the post rest amplitude in relation to the ...

Calsequestrin is the principal calcium-binding protein present in the sarcoplasmic reticulum of cardiac and skeletal muscle [(PUBMED:3379055)]. It is a highly acidic protein that is able to bind over 40 calcium ions and acts as an internal calcium store in muscle. Sequence analysis has suggested that calcium is not bound in distinct pockets via EF-hand motifs, but rather via presentation of a charged protein surface. Two forms of calsequestrin have been identified. The cardiac form is present in cardiac and slow skeletal muscle and the fast skeletal form is found in fast skeletal muscle. The release of calsequestrin-bound calcium (through a a calcium release channel) triggers muscle contraction. The active protein is not highly structured, more than 50% of it adopting a random coil conformation [(PUBMED:3427023)]. When calcium binds there is a structural change whereby the alpha-helical content of the protein increases from 3 to 11% [(PUBMED:3427023)]. Both forms of calsequestrin are ...

Reversibly inhibits the activity of ATP2A2 in cardiac sarcoplasmic reticulum by decreasing the apparent affinity of the ATPase for Ca(2+). Modulates the contractility of the heart muscle in response to physiological stimuli via its effects on ATP2A2. Modulates calcium re-uptake during muscle relaxation and plays an important role in calcium homeostasis in the heart muscle. The degree of ATP2A2 inhibition depends on the oligomeric state of PLN. ATP2A2 inhibition is alleviated by PLN phosphorylation (By similarity).

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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 ...

mouse Asph protein: 26-kDa protein isolated from cardiac junctional sarcoplasmic reticulum; hydroxylates ASP or ASN residues in EGF domains of some proteins; RefSeq NM_023066

In human disease and experimental animal models, depressed Ca2+ handling in failing cardiomyocytes is widely attributed to impaired sarcoplasmic reticulum (SR) function. In mice, disruption of the PLN gene encoding phospholamban (PLN) or expression of dominant-negative PLN mutants enhances SR and cardiac function, but effects of PLN mutations in humans are unknown. Here, a T116G point mutation, substituting a termination codon for Leu-39 (L39stop), was identified in two families with hereditary heart failure. The heterozygous individuals exhibited hypertrophy without diminished contractile performance. Strikingly, both individuals homozygous for L39stop developed dilated cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and 27. An over 50% reduction in PLN mRNA and no detectable PLN protein were noted in one explanted heart. The expression of recombinant PLN-L39stop in human embryonic kidney (HEK) 293 cells and adult rat cardiomyocytes showed no PLN inhibition of SR ...

In human disease and experimental animal models, depressed Ca2+ handling in failing cardiomyocytes is widely attributed to impaired sarcoplasmic reticulum (SR) function. In mice, disruption of the PLN gene encoding phospholamban (PLN) or expression of dominant-negative PLN mutants enhances SR and cardiac function, but effects of PLN mutations in humans are unknown. Here, a T116G point mutation, substituting a termination codon for Leu-39 (L39stop), was identified in two families with hereditary heart failure. The heterozygous individuals exhibited hypertrophy without diminished contractile performance. Strikingly, both individuals homozygous for L39stop developed dilated cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and 27. An over 50% reduction in PLN mRNA and no detectable PLN protein were noted in one explanted heart. The expression of recombinant PLN-L39stop in human embryonic kidney (HEK) 293 cells and adult rat cardiomyocytes showed no PLN inhibition of SR ...

ABSTRACT: We construct a detailed mathematical model for Ca2+ regulation in the ventricular myocyte that includes novel descriptions of subcellular mechanisms based on recent experimental findings: 1) the Keizer-Levine model for the ryanodine receptor (RyR), which displays adaptation at elevated Ca2+; 2) a model for the L-type Ca2+ channel that inactivates by mode switching; and 3) a restricted subspace into which the RyRs and L-type Ca2+ channels empty and interact via Ca2+. We add membrane currents from the Luo-Rudy Phase II ventricular cell model to our description of Ca2+ handling to formulate a new model for ventricular action potentials and Ca2+ regulation. The model can simulate Ca2+ transients during an action potential similar to those seen experimentally. The subspace [Ca2+] rises more rapidly and reaches a higher level (10-30 microM) than the bulk myoplasmic Ca2+ (peak [Ca2+]i approximately 1 microM). Termination of sarcoplasmic reticulum (SR) Ca2+ release is predominately due to ...

So says Yasser A. Mahmmoud of the University of Aarhus in Denmark: In muscle cells the sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA) couples the free energy of ATP hydrolysis to pump Ca2+ ions from the cytoplasm to the SR lumen. In addition, SERCA plays a key role in non-shivering thermogenesis through uncoupled reactions, where ATP hydrolysis takes place without active Ca2+ […]

This gene encodes one of the SERCA Ca(2+)-ATPases, which are intracellular pumps located in the sarcoplasmic or endoplasmic reticula of muscle cells. This enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen, and is involved in calcium sequestration associated with muscular excitation and contraction. Alternative splicing results in multiple transcript variants encoding different isoforms.

The ERRα transcriptional pathway has been shown in recent years to play a central role in the regulation of mitochondrial energy metabolism in many cell and tissue types, including striated muscle (20, 63). In the present study, we explored the hypothesis that ERRα may function more broadly as an essential regulatory component of myogenesis. Myocyte differentiation requires precise regulation of multiple gene programs, consisting of genes encoding contractile and sarcoplasmic reticulum proteins, along with ubiquitously expressed proteins involved in energy metabolism. Such coordination may be mediated by transcriptional regulators of energy metabolism genes, including the ERR isoforms and their PGC-1 coactivators, that are temporally induced as part of the myogenic program (Refs. 28, 66; present study). Our findings suggest that ERRα does promote differentiation when overexpressed and is required for normal myogenesis. A surprising finding was that the broader regulatory function for ERRα in ...

A molecular ribbon model of a calcium pump, a structure responsible for coordinating muscular contraction or signalling other cells along the cell membrane. Calcium pumps are embedded in the sarcoplasmic reticulum of muscle cells, transferring two calcium ions for each molecule of ATP broken down. - Stock Image C017/6296

Phospholamban (PLN) is an integral membrane protein that regulates calcium homeostasis by inhibiting sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA) in cardiac muscle. PLN exists in two primary oligomeric forms: (1) a monomer that directly bind

TY - JOUR. T1 - Effects of Melittin on Molecular Dynamics and Ca-ATPase Activity in Sarcoplasmic Reticulum Membranes. T2 - Electron Paramagnetic Resonance. AU - Mahaney, James E.. AU - Thomas, David D. PY - 1991/7/1. Y1 - 1991/7/1. N2 - We have performed electron paramagnetic resonance (EPR) experiments on nitroxide spin labels incorporated into rabbit skeletal sarcoplasmic reticulum (SR), in order to investigate the physical and functional interactions between melittin, a small basic membrane-binding peptide, and the Ca-ATPase of SR. Melittin binding to SR substantially inhibits Ca2+-dependent ATPase activity at 25 °C, with half-maximal inhibition at 9 mol of melittin bound per mole of Ca-ATPase. Saturation transfer EPR (ST-EPR) of maleimide spin-labeled Ca-ATPase showed that melittin decreases the submillisecond rotational mobility of the enzyme, with a 4-fold increase in the effective rotational correlation time (τr) at a melittin/Ca-ATPase mole ratio of 10:1. This decreased rotational ...

ANA M. MATA, ANN E. SCHOFIELD, JANE WOODBINE, ANTHONY G. LEE, J. MALCOLM EAST; Probing the nucleotide binding site of sarcoplasmic reticulum (Ca2+ -Mg2)-ATPase with anti-fluorescein antibodies. Biochem Soc Trans 1 December 1989; 17 (6): 1105-1106. doi: https://doi.org/10.1042/bst0171105. Download citation file:. ...

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

The effect of cardiac glycosides to increase cardiac inotropy by altering Ca2+ cycling is well known but still poorly understood. The studies described in this report focus on defining the effects of ouabain signaling on sarcoplasmic reticulum Ca2+-ATPase function. Rat cardiac myocytes treated with 50 μM ouabain demonstrated substantial increases in systolic and diastolic Ca2+ concentrations. The recovery time constant for the Ca2+ transient, τ, was significantly prolonged by ouabain. Exposure to 10 μM H2O2, which causes an increase in intracellular reactive oxygen species similar to that of 50 μM ouabain, caused a similar increase in τ. Concurrent exposure to 10 mM N-acetylcysteine or an aqueous extract from green tea (50 mg/ml) both prevented the increases in τ as well as the changes in systolic or diastolic Ca2+ concentrations. We also observed that 50 μM ouabain induced increases in developed pressure in addition to diastolic dysfunction in the isolated perfused rat heart. Coadministration of

Read Sarcoplasmic Reticulum Phospholipid Fatty Acid Composition and Sarcolipin Content in Rat Skeletal Muscle, The Journal of Membrane Biology on DeepDyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips.

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

TY - JOUR. T1 - Characterization of the ATP-binding domain of the sarco(endo)plasmic reticulum Ca2+-ATPase. T2 - Probing nucleotide binding by multidimensional NMR. AU - Abu-Abed, Mona. AU - Mal, Tapas K.. AU - Kainosho, Masatsune. AU - MacLennan, David H.. AU - Ikura, Mitsuhiko. PY - 2002/1/29. Y1 - 2002/1/29. N2 - The skeletal muscle sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA1a) mediates muscle relaxation by pumping Ca2+ from the cytosol to the ER/SR lumen. In efforts aimed at understanding the structural basis for the conformational changes accompanying the reaction cycle catalyzed by SERCA1a, we have studied the ATP-binding domain of SERCA1a in both nucleotide-bound and -free forms by NMR. Limited proteolysis analyses guided us to express a 28 kDa stably folded fragment containing the nucleotide-binding domain of SERCA1a spanning residues Thr357-Leu600. ATP binding activity was demonstrated for this fragment by a FITC competition assay. A nearly complete backbone resonance assignment of ...

The mechanisms that terminate \(Ca^{2+}\) release from the sarcoplasmic reticulum are not fully understood. D4cpv-Casq1 (Sztretye et al. 2011. J. Gen. Physiol. doi:10.1085/jgp.201010591) was used in mouse skeletal muscle cells under voltage clamp to measure free \(Ca^{2+}\) concentration inside the sarcoplasmic reticulum (SR), \([Ca^{2+}]_{SR}\), simultaneously with that in the cytosol, \([Ca^{2+}]_c\), during the response to long-lasting depolarization of the plasma membrane. The ratio of \(Ca^{2+}\) release flux (derived from \([Ca^{2+}]_c(t)\)) over the gradient that drives it (essentially equal to \([Ca^{2+}]_{SR}\)) provided directly, for the first time, a dynamic measure of the permeability to \(Ca^{2+}\) of the releasing SR membrane. During maximal depolarization, flux rapidly rises to a peak and then decays. Before 0.5 s, \([Ca^{2+}]_{SR}\) stabilized at ~35% of its resting level; depletion was therefore incomplete. By 0.4 s of depolarization, the measured permeability decayed to ~10% of ...

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 ...

BACKGROUND: Impaired sarcoplasmic reticular Ca(2+) uptake resulting from decreased sarcoplasmic reticulum Ca(2+)-ATPase type 2a (SERCA2a) expression or activity is a characteristic of heart failure with its associated ventricular arrhythmias. Recent attempts at gene therapy of these conditions explored strategies enhancing SERCA2a expression and the activity as novel approaches to heart failure management. We here explore the role of Pak1 in maintaining ventricular Ca(2+) homeostasis and electrophysiological stability under both normal physiological and acute and chronic β-adrenergic stress conditions. METHODS AND RESULTS: Mice with a cardiomyocyte-specific Pak1 deletion (Pak1(cko)), but not controls (Pak1(f/f)), showed high incidences of ventricular arrhythmias and electrophysiological instability during either acute β-adrenergic or chronic β-adrenergic stress leading to hypertrophy, induced by isoproterenol. Isolated Pak1(cko) ventricular myocytes correspondingly showed aberrant cellular Ca(2+)

Junctophilin 2, also known as JPH2, is a protein which in humans is encoded by the JPH2 gene. Alternative splicing has been observed at this locus and two variants encoding distinct isoforms are described. Junctional complexes between the plasma membrane and endoplasmic/sarcoplasmic reticulum are a common feature of all excitable cell types and mediate cross talk between cell surface and intracellular ion channels. The protein encoded by this gene is a component of junctional complexes and is composed of a C-terminal hydrophobic segment spanning the endoplasmic/sarcoplasmic reticulum membrane and a remaining cytoplasmic membrane occupation and recognition nexus (MORN) domain that shows specific affinity for the plasma membrane. JPH2 is a member of the junctophilin gene family (the other members of the family are JPH1, JPH3, and JPH4) and is the predominant isoform in cardiac tissue, but is also expressed with JPH1 in skeletal muscle. The JPH2 protein product plays a critical role in maintaining ...

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 ...

This study describes the biochemical composition of junctional feet in skeletal muscle utilizing a fraction of isolated triad junctions. [3H]Ouabain entrapment was employed as a specific marker for T-tubules. The integrity of the triad junction was assayed by the isopycnic density of [3H]ouabain activity (24-30% sucrose for free T-tubules, 38-42% sucrose for intact triads). Trypsin, chymotrypsin, and pronase all caused separation of T-tubules from terminal cisternae, indicating that the junction is composed as least in part of protein. Trypsin and chymotrypsin hydrolyzed four proteins: the Ca2+ pump, a doublet 325,000, 300,000, and an 80,000 Mr protein. T-tubules which had been labeled covalently with 125I were joined to unlabeled terminal cisternae by treatment with K cacodylate. The reformed triads were separated from free T-tubules and then severed by passage through a French press. When terminal cisternae were separated from T-tubules, some 125I label was transferred from the labeled ...

Cardiac arrhythmias can be triggered from ischaemic cardiac muscle due to the damage inflicted on individual myocytes. During an ischaemic episode free fatty acids accumulate in the ischaemic tissue. The importance of these fatty acids lies in the apparent ability of some classes of fatty acid to protect against cardiac arrhythmias. As cardiac sudden death is a likely cause of death in patients who have suffered an initial ischaemic insult, protection against such arrhythmias may be of crucial importance. The following review discusses how this protection may be produced, dealing specifically with changes in electrophysiological properties of cells and intracellular calcium regulation. ...

FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. The encoded protein is highly expressed in various brain regions and cardiac and skeletal muscle. It is specifically localized to the sarcoplasmic reticulum and nuclear membrane, and is involved in anchoring PKA to the nuclear membrane or sarcoplasmic reticulum. [provided by RefSeq, Jul 2008 ...

FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. The encoded protein is highly expressed in various brain regions and cardiac and skeletal muscle. It is specifically localized to the sarcoplasmic reticulum and nuclear membrane, and is involved in anchoring PKA to the nuclear membrane or sarcoplasmic reticulum. [provided by RefSeq, Jul 2008 ...

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

RPG374Mu01, Recombinant ATPase, Ca++ Transporting, Cardiac Muscle, Slow Twitch 2 (ATP2A2), ATP2B; DAR; SERCA2; Calcium pump 2; Endoplasmic reticulum class 1/2 Ca(2+) ATPase; Calcium-transporting ATPase sarcoplasmic reticulum type, slow twitch skeletal muscle | Products for research use only!

Buy our Recombinant Human Phospholamban protein. Ab114227 is a protein fragment produced in Wheat germ and has been validated in WB, ELISA, SDS-PAGE. Abcam…

Hospitalizations for acute heart failure are associated with high mortality and readmission rates. Ten to 20% of the patients have signs of low cardiac output and fluid overload. The administration of inotropic agents to correct these hemodynamic abnormalities may be indicated in these patients. However, the risk to benefit ratio of inotropic agents is high and an increase of untoward effects and mortality has been suggested by many retrospective analyses and meta-analyses. Limitations of inotropic therapy seem mainly related to their mechanisms of action based, in the case of the traditional agents, on an increase in intracellular cyclic AMP and calcium concentrations. Concomitant peripheral vasodilation, such as in the case of the novel agent levosimendan is another important limitation, above when patients are hypotensive and/or treated with vasodilators and high doses of diuretics. Myosin activators, histaroxime, sarcoplasmic reticulum ATPase activators and metabolic agents seem promising as active

Although altered atrial Ca2+ homeostasis contributes to electrical and contractile remodeling in AF,1 the underlying cellular mechanisms are poorly understood. Current concepts propose that disturbed function of Ca2+ handling and myofilament proteins may result from changes in their phosphorylation levels. The higher PKA phosphorylation of RyR2 in cAF than in SR20 is associated with enhanced single RyR2 activity and larger spontaneous Ca2+ release from sarcoplasmic reticulum.21 This together with the larger influx of Ca2+ via ICa,L (less influx of Ca2+ per beat but more beats per time unit) is consistent with the Ca2+-overload hypothesis in AF (Figure 8).1 Because cAF is associated with enhanced phosphorylation of PLB and reduced expression of sarcolipin,32 another endogenous Serca2a inhibitor, Serca2a function is probably increased, compensating for the diastolic Ca2+ leak through RyR2 channels.20. The greater phosphorylation of PLB at Thr-17 in cAF compared with SR despite increased total PP ...

TY - JOUR. T1 - β-Adrenergic induced SR Ca2 + leak is mediated by an Epac-NOS pathway. AU - Pereira, Laëtitia. AU - Bare, Dan J.. AU - Galice, Samuel. AU - Shannon, Thomas R.. AU - Bers, Donald M. PY - 2017/7/1. Y1 - 2017/7/1. N2 - Cardiac β-adrenergic receptors (β-AR) and Ca2 +-Calmodulin dependent protein kinase (CaMKII) regulate both physiological and pathophysiological Ca2 + signaling. Elevated diastolic Ca2 + leak from the sarcoplasmic reticulum (SR) contributes to contractile dysfunction in heart failure and to arrhythmogenesis. β-AR activation is known to increase SR Ca2 + 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). Here we tested whether Epac and NOS function in a single series pathway to increase β-AR induced and CaMKII-dependent SR Ca2 + ...

F49 Molecular Cloning and Sequencing of the HRC Gene from Mouse Heart Reveals a Highly Unstable GAG Repeat. Shundi Shi, Steven R. Brunnert. Columbia University, Institute of Comparative Medicine 630 W. 168th Street, Mail Box 17, New York, NY 10032. Histidine-rich calcium binding protein (HRC) is a luminal sarcoplasmic reticulum protein that has been mapped to human Chromosome 19 and mouse Chromosome 7 and considered a candidate gene of several genetic diseases in humans and mice. We derived a 2407-bp clone encoding for a 738 AA protein by PCR from C57BL/6J mouse heart and found a highly unstable GAG repeat in the middle of the coding region. The instability of the GAG repeat could be detected within individual C57BL/6J and DBA/2J mice in both genomic DNA and cDNA, and no polymorphism was found between two mouse HRC cDNAs except the unstable GAG repeats. At normal physiologic conditions, no GAG expansion was found in the unstable GAG repeat region in the dystrophic cardiac calcinosis (DCC) ...

Heart failure (HF) patients are a medically complex and heterogeneous population with multiple cardiac and non-cardiac comorbidities. Although there are a multitude of etiologic substrates and initiating and amplifying mechanisms contributing to disease progression, these pathophysiologic processes ultimately all lead to impaired myocardial function. The myocardium must both pump oxygenated, nutrient-rich blood throughout the body (systolic function) and receive deoxygenated, nutrient-poor blood returning from the periphery (diastolic function). At the molecular level, it is well-established that Ca2+ plays a central role in excitation-contracting coupling with action potentials stimulating the opening of L-type Ca2+ in the plasma membrane and ryanodine receptor 2 (RyR2) in the sarcoplasmic reticulum (SR) membrane during systole and the Na-Ca2+ exchanger and SERCA2a returning Ca2+ to the extracellular space and SR, respectively, during diastole. However, there is increasing recognition that ...

Phospholamban-associated cardiomyopathy is an inherited cardiomyopathy, characterised by a defect in regulation of the sarcoplasmic reticulum Ca 2+

Ca(2+) signaling regulates cell function. This is subject to modulation by H(+) ions that are universal end-products of metabolism. Due to slow diffusion and common buffers, changes in cytoplasmic [Ca(2+)] ([Ca(2+)]i) or [H(+)] ([H(+)]i) can become compartmentalized, leading potentially to complex spatial Ca(2+)/H(+) coupling. This was studied by fluorescence imaging of cardiac myocytes. An increase in [H(+)]i, produced by superfusion of acetate (salt of membrane-permeant weak acid), evoked a [Ca(2+)]i rise, independent of sarcolemmal Ca(2+) influx or release from mitochondria, sarcoplasmic reticulum, or acidic stores. Photolytic H(+) uncaging from 2-nitrobenzaldehyde also raised [Ca(2+)]i, and the yield was reduced following inhibition of glycolysis or mitochondrial respiration. H(+) uncaging into buffer mixtures in vitro demonstrated that Ca(2+) unloading from proteins, histidyl dipeptides (HDPs; e.g., carnosine), and ATP can underlie the H(+)-evoked [Ca(2+)]i rise. Raising [H(+)]i tonically at one

This review summarizes estimates for cytoplasmic-free concentrations of Ca,SUP,2+,/SUP, ([Ca,SUP,2+,/SUP,],SUB,i,/SUB,) and Mg,SUP,2+,/SUP, ([Mg,SUP,2+,/SUP,],SUB,i,/SUB,) at rest and during contraction of skeletal muscles, from which substantial quantitative information about them has been accumulated. Although the estimates of resting [Ca,SUP,2+,/SUP,],SUB,i,/SUB, in the literature widely differ, which is because of the variety of difficulties related to different methodologies used, recent studies suggest that estimates of resting [Ca,SUP,2+,/SUP,],SUB,i,/SUB, of approximately 0.05-0.1 μM are likely to be correct. Following action potential propagation, the Ca,SUP,2+,/SUP, release from the sarcoplasmic reticulum causes a transient rise of [Ca,SUP,2+,/SUP,],SUB,i,/SUB, (Ca,SUP,2+,/SUP, transient). The large peak amplitude and brief time course of the Ca,SUP,2+,/SUP, transients have been established only recently by studies with low-affinity Ca,SUP,2+,/SUP, indicators developed in the past ...

T-tubule structural abnormalities in myotubularin morphant muscle.T-tubule (vertical arrows) and sarcoplasmic reticulum (angled arrows) abnormalities as demonst

The 650 skeletal muscles within the human physique contract when they obtain indicators from motor neurons, that are triggered from part of the cell called the sarcoplasmic reticulum. Influences equivalent to loopy bulk can permit you to move up from a mean bodybuilder to any individual thats commonly known as a picture within the business and might be good on your coaching. Breathing difficulty is a typical symptom of heart or lung disease ...

Does sarcoplasmic hypertrophy happen and, if so, whats the effect on overall muscle growth? We take a second look at sarcoplasmic hypertrophy.

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1SJI: Comparing skeletal and cardiac calsequestrin structures and their calcium binding: a proposed mechanism for coupled calcium binding and protein polymerization.

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