Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type 2 ryanodine receptor (RyR2) is the major calcium release channel in cardiac muscle. Phosphorylation of RyR2 by cAMP-dependent protein kinase A and by calmodulin-dependent protein kinase II modulates channel activity. Hyperphosphorylation at a single amino acid residue, Ser-2808, has been proposed to directly disrupt the binding of a 12.6-kDa FK506-binding protein (FKBP12.6) to RyR2, causing a RyR2 malfunction that triggers cardiac arrhythmias in human heart failure. To determine the structural basis of the interaction between Ser-2808 and FKBP12.6, we have employed two independent approaches to map this phosphorylation site in RyR2 by three-dimensional cryo-electron microscopy. In one approach, we inserted a green fluorescent protein (GFP) after amino acid Tyr-2801, and mapped the GFP three-dimensional location in the RyR2 structure. In another approach, the binding site of monoclonal antibody 34C was mapped in the three-dimensional structure of skeletal muscle RyR1. The epitope of antibody 34C has been mapped to amino acid residues 2,756 through 2,803 of the RyR1 sequence, corresponding to residues 2,722 through 2,769 of the RyR2 sequence. These locations of GFP insertion and antibody binding are adjacent to one another in domain 6 of the cytoplasmic clamp region. Importantly, the three-dimensional location of the Ser-2808 phosphorylation site is 105-120 A distance from the FKBP12.6 binding site mapped previously, indicating that Ser-2808 is unlikely to be directly involved in the binding of FKBP12.6 to RyR2, as had been proposed previously.
 ...
PMID:Three-dimensional localization of serine 2808, a phosphorylation site in cardiac ryanodine receptor. 1760 10

Cyclic nucleotide second messages (cAMP and cGMP) play a central role in signal transduction and regulation of physiologic responses. The only way to inactivate them is to degrade them through the action of phosphodiesterases (PDEs). Recent advances show that PDE4, a cAMP specific phosphodiesterase, has specific functions in regulating the activities of the cardiovascular system. PDE4 is expressed in the cells of cardiovascular systems including cardiomyocytes, vascular smooth muscle cells, and vascular endothelial cells. The expression level of PDE4 is shown to be downregulated in the failure hearts, while it is upregulated in hypertrophied hearts. And PDE4 deficiency in mice is associated with a cardiac phenotype comprised of a progressive, age-related cardiomyopathy, accelerated heart failure after myocardial infarction and exercise-induced arrhythmias. Local levels of cAMP regulate the precise opening of the ryanodine receptor complex (RyR2) which releases calcium at the start of a heartbeat. Loss or inhibition of PDE4 activity increases calcium flow through RyR2, and causes leakiness and heart failure in mice. These finding may show us a new target for treating cardiovascular diseases.
 ...
PMID:[Cyclic nucleotide phosphodiesterase IV expression, activity and targeting in cells of cardiovascular system]. 1770 90

Increased phosphorylation of the cardiac ryanodine receptor (RyR)2 by protein kinase A (PKA) at the phosphoepitope encompassing Ser2808 has been advanced as a central mechanism in the pathogenesis of cardiac arrhythmias and heart failure. In this scheme, persistent activation of the sympathetic system during chronic stress leads to PKA "hyperphosphorylation" of RyR2-S2808, which increases Ca2+ release by augmenting the sensitivity of the RyR2 channel to diastolic Ca2+. This gain-of-function is postulated to occur with the unique participation of RyR2-S2808, and other potential PKA phosphorylation sites have been discarded. Although it is clear that RyR2 is among the first proteins in the heart to be phosphorylated by beta-adrenergic stimulation, the functional impact of phosphorylation in excitation-contraction coupling and cardiac performance remains unclear. We used gene targeting to produce a mouse model with complete ablation of the RyR2-S2808 phosphorylation site (RyR2-S2808A). Whole-heart and isolated cardiomyocyte experiments were performed to test the role of beta-adrenergic stimulation and PKA phosphorylation of Ser2808 in heart failure progression and cellular Ca2+ handling. We found that the RyR2-S2808A mutation does not alter the beta-adrenergic response, leaves cellular function almost unchanged, and offers no significant protection in the maladaptive cardiac remodeling induced by chronic stress. Moreover, the RyR2-S2808A mutation appears to modify single-channel activity, although modestly and only at activating [Ca2+]. Taken together, these results reveal some of the most important effects of PKA phosphorylation of RyR2 but do not support a major role for RyR2-S2808 phosphorylation in the pathogenesis of cardiac dysfunction and failure.
 ...
PMID:Intact beta-adrenergic response and unmodified progression toward heart failure in mice with genetic ablation of a major protein kinase A phosphorylation site in the cardiac ryanodine receptor. 1793 30

In this study, we investigated the role of elevated sarcoplasmic reticulum (SR) Ca(2+) leak through ryanodine receptors (RyR2s) in heart failure (HF)-related abnormalities of intracellular Ca(2+) handling, using a canine model of chronic HF. The cytosolic Ca(2+) transients were reduced in amplitude and slowed in duration in HF myocytes compared with control, changes paralleled by a dramatic reduction in the total SR Ca(2+) content. Direct measurements of [Ca(2+)](SR) in both intact and permeabilized cardiac myocytes demonstrated that SR luminal [Ca(2+)] is markedly lowered in HF, suggesting that alterations in Ca(2+) transport rather than fractional SR volume reduction accounts for the diminished Ca(2+) release capacity of SR in HF. SR Ca(2+) ATPase (SERCA2)-mediated SR Ca(2+) uptake rate was not significantly altered, and Na(+)/Ca(2+) exchange activity was accelerated in HF myocytes. At the same time, SR Ca(2+) leak, measured directly as a loss of [Ca(2+)](SR) after inhibition of SERCA2 by thapsigargin, was markedly enhanced in HF myocytes. Moreover, the reduced [Ca(2+)](SR) in HF myocytes could be nearly completely restored by the RyR2 channel blocker ruthenium red. The effects of HF on cytosolic and SR luminal Ca(2+) signals could be reasonably well mimicked by the RyR2 channel agonist caffeine. Taken together, these results suggest that RyR2-mediated SR Ca(2+) leak is a major factor in the abnormal intracellular Ca(2+) handling that critically contributes to the reduced SR Ca(2+) content of failing cardiomyocytes.
 ...
PMID:Enhanced ryanodine receptor-mediated calcium leak determines reduced sarcoplasmic reticulum calcium content in chronic canine heart failure. 1782 26

Ventricular arrhythmias deteriorating into sudden cardiac death are a major cause of mortality worldwide. The recent linkage of a genetic form of cardiac arrhythmia to mutations in the gene encoding RyR2 (ryanodine receptor 2) has uncovered an important role of this SR (sarcoplasmic reticulum) calcium release channel in triggering arrhythmias. Mutant RyR2 channels give rise to spontaneous release of calcium (Ca(2+)) from the SR during diastole, which enhances the probability of ventricular arrhythmias. Several molecular mechanisms have been proposed to explain the gain-of-function phenotype observed in mutant RyR2 channels. Despite considerable differences between the models discussed in the present review, each predicts spontaneous diastolic Ca(2+) leak from the SR due to incomplete closure of the RyR2 channel. Enhanced SR Ca(2+) leak is also observed in common structural diseases of the heart, such as heart failure. In heart failure, defective channel regulation in the absence of inherited mutations may also increase SR Ca(2+) leak and initiate cardiac arrhythmias. Therefore inhibition of diastolic Ca(2+) leak through SR Ca(2+) release channels has emerged as a new and promising therapeutic target for cardiac arrhythmias.
 ...
PMID:Sarcoplasmic reticulum calcium leak and cardiac arrhythmias. 1795 53

The cardiac ryanodine receptor (RyR2) is the sarcoplasmic reticulum (SR) Ca(2+) release channel which is responsible for generation of the cytosolic Ca(2+) transient required for activation of cardiac contraction. RyR2 functional activity is governed by changes in [Ca(2+)] on both the cytosolic and luminal phase of the RyR2 channel. Activation of RyR2 by cytosolic Ca(2+) results in Ca(2+)-induced Ca(2+) release (CICR) from the SR. The decline in luminal [Ca(2+)] following release contributes to termination of CICR and Ca(2+) signalling refractoriness through the process of luminal Ca(2+)-dependent deactivation of RyR2s. The control of RyR2s by luminal Ca(2+) involves coordinated interaction of the channel with several SR proteins, including the Ca(2+)-binding protein calsequestrin (CASQ2), and the integral proteins triadin 1 (TRD) and junctin (JCN). CASQ2 in addition to serving as a Ca(2+) storage site and a luminal Ca(2+) buffer modulates RyR2 function more directly as a putative luminal Ca(2+) sensor. TRD and JCN, stimulatory by themselves, mediate the interactions between CASQ2 and RyR2. Acquired and genetic defects in proteins of this junctional Ca(2+) signalling complex lead to disease states such as cardiac arrhythmia and heart failure by impairing luminal Ca(2+) regulation of RyR2.
 ...
PMID:Modulation of ryanodine receptor by luminal calcium and accessory proteins in health and cardiac disease. 1800 56

Nitric oxide (NO) is a highly reactive, free radical signalling molecule that is constitutively released in cardiomyocytes by both the endothelial and neuronal isoforms of nitric oxide synthase (eNOS and nNOS, respectively). There are increasing data indicating that NO modulates various proteins involved in excitation-contraction coupling (ECC), and here we discuss the evidence that NO may modulate the function of the ryanodine receptor Ca(2+) release channel (RyR2) on the cardiac sarcoplasmic reticulum (SR). Both constitutive isoforms of NOS have been shown to co-immunoprecipitate with RyR2, suggesting that the channel may be a target protein for NO. eNOS gene deletion has been shown to abolish the increase in spontaneous Ca(2+) spark frequency in cardiomyocytes exposed to sustained stretch, whereas the effect of nNOS-derived NO on RyR2 function remains to be investigated. Single channel studies have been performed with RyR2 reconstituted in planar lipid bilayers and exposed to various NO donors and, under these conditions, NO appears to have a dose-dependent, stimulatory effect on channel open probability (P(open)). We discuss whether NO has a direct effect on RyR2 via covalent S-nitrosylation of reactive thiol residues within the protein, or whether there are downstream effects via cyclic nucleotides, phosphodiesterases, and protein kinases. Finally, we consider whether the proposed migration of nNOS from the SR to the sarcolemma in the failing heart may have consequences for the nitrosative vs. oxidative balance at the level of the RyR2, and whether this may contribute to an increased diastolic Ca(2+) leak, depleted SR Ca(2+) store, and reduced contractility in heart failure.
 ...
PMID:Does nitric oxide modulate cardiac ryanodine receptor function? Implications for excitation-contraction coupling. 1800 80

Heart failure (HF) is a chronic multi-factorial disease characterized by sarcoplasmic reticulum (SR) dysfunction that manifests as severely reduced contractility and increased risk of arrhythmia. Several lines of evidence have revealed the existence of defective ryanodine receptor (RyR2)-mediated Ca(2+) leak in HF, although its relevance as a causative factor rather than a phenotypic consequence of the disease is questioned. This review will consider the relative contribution of RyR2-mediated Ca(2+) leak to the profound cellular, transcriptional and electrical remodelling associated with HF. In particular, it will focus on our current understanding of the role of defective phosphorylation of RyR2 as a both a chronic mediator of excitation-contraction coupling (ECC) dysfunction and as a potent catalyst of RyR2-dependent arrhythmogenesis. A hypothetical concept that SR Ca(2+) leak fundamentally underlies the increased arrhythmogenic susceptibility in HF, but that it may not directly contribute to contractile dysfunction, which may involve maladaptive perturbations in metabolism and energy utilization, is also discussed.
 ...
PMID:Sarcoplasmic reticulum Ca2+ leak in heart failure: mere observation or functional relevance? 1800 86

Sudden cardiac death (SCD) remains a major cause of mortality, and despite our knowledge of the causative genetic, molecular and biochemical cellular mechanisms involved, effective therapeutic strategies are lacking. Perturbations in cardiac Ca2+ handling promote arrhythmias and there is enormous interest in developing new anti-arrhythmics aimed at correcting Ca2+ release dysfunction. In particular, abnormal Ca2+ release arising as a result of acquired or genetic defects in cardiac ryanodine receptors (RyR2) has emerged as an important arrhythmogenic trigger in heart failure, and in a devastating genetic arrhythmia syndrome termed catecholaminergic polymorphic ventricular tachycardia (CPVT). Here, we evaluate how experimental insights into RyR2 structure-function are unravelling the precise molecular basis of channel dysfunction and are advancing the development of new therapeutic strategies. We also discuss the functional role of RyR2 in the context of the exquisite synergism existing between numerous cellular components involved in cardiac Ca2+ signalling, and how these complex interactions may be used to design new anti-arrhythmic approaches that target multiple facets of RyR2 regulation.
 ...
PMID:Developing new anti-arrhythmics: clues from the molecular basis of cardiac ryanodine receptor (RyR2) Ca2+-release channel dysfunction. 1804 69

In excitable cells such as skeletal and cardiac myocytes excitation-contraction coupling is an important intermediate step between initiation of the action potential and induction of contraction. This process is predominantly controlled by Ca(2+) release from the sarcoplasmic reticulum via the ryanodine receptor. This very large protein (MW 560 kDa) exists as a homotetramer (~2.2 MDa) and is expressed in three isoforms: RyR1, expressed in skeletal muscle; RyR2, expressed in cardiac muscle; and RyR3, expressed in various cells at lower levels than the other isoforms. Release of Ca(2+) via RyR2 is induced by Ca(2+) influx through L-type Ca(2+) channels and is modulated by multiple factors, including phosphorylation of RyR2 protein by protein kinase A, calmodulin kinase II and FKBP12.6, and stimulation via the beta-adrenergic receptor signaling pathway. Hyperphosphorylation of RyR2 induces Ca(2+) leak during diastole, which can cause fatal arrhythmias and lead to heart failure. This makes RyR2 an important therapeutic target. Although there are few commercially available drugs that inhibit Ca(2+) leak from RyR2, K201 (JTV-519), a benzothiazepine derivative, has emerged as a new ryanodine receptor-selective agent that prevents atrial fibrillation, ventricular arrhythmias, heart failure and exercise-induced sudden cardiac death. In this review, we discuss recent advances in our understanding of the basic structure and function of ryanodine receptors, their involvement in heart disease, and the development of drugs to prevent ryanodine receptor malfunction and recent patents.
 ...
PMID:Ryanodine receptor: a novel therapeutic target in heart disease. 1822 Nov 9


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>