Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 of PKA. Consistent with this, single-channel studies demonstrate that EPA (10-100 microM), but not saturated fatty acids, reduce the open probability (Po) of the cardiac RyR incorporated into phospholipid bilayers. EPA also inhibited the binding of [3H]ryanodine to isolated heavy SR. Our results indicate that direct inhibition of RyR channel gating by PUFAs play an important role in the overall antiarrhythmic properties of these compounds.
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PMID:Effects of eicosapentaenoic acid on cardiac SR Ca(2+)-release and ryanodine receptor function. 1461 63

In cardiac muscle, the ryanodine receptor (RyR2) on the sarcoplasmic reticulum (SR) releases the calcium required for muscle contraction. The magnitude of Ca(2+) release by RyR2, which is subject to regulation by several physiological mediators, determines cardiac contractility. In heart failure, chronic stimulation of the beta-adrenergic signaling pathway leads to hyperphosphorylation of RyR2 by protein kinase A, which dissociates calstabin2 (FKBP12.6) from the receptor. Calstabin2-depleted channels display altered channel gating and can cause diastolic Ca(2+) release from the SR. This release depletes the SR Ca(2+) stores, leading to reduced myocardial contractility. Mutant RyR2, found in patients with catecholaminergic polymorphic ventricular tachycardia, has decreased calstabin2 binding affinity, which can trigger ventricular arrhythmias and sudden cardiac death after stress and exercise. Thus, defects in RyR2 have been linked to heart failure and exercise-induced sudden cardiac death and might provide novel therapeutic targets for the treatment of these common diseases of the heart.
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PMID:Altered function and regulation of cardiac ryanodine receptors in cardiac disease. 1465 99

An endocrine disruptor chemical, bisphenol-A (BPA), is reported to have several short-term actions in various tissues and/or cells; however, the mechanisms of these actions have not been fully elucidated. We investigated short-term actions evoked by BPA in pheochromocytoma PC12 cells. BPA elicited dopamine release in PC12 cells in a dose-dependent manner. A selective N-type calcium channel antagonist (omega-conotoxin GVIA) and a ryanodine receptor blocker (ryanodine) inhibited the BPA-induced dopamine release. The expression of ryanodine receptor mRNA was detected by RT-PCR in PC12 cells. Subsequently, in order to prove whether membrane receptors participate in BPA-evoked dopamine release, a guanine nucleotide-binding protein inhibitor [guanosine 5'-(beta-thio) diphosphate], cyclic AMP antagonist (Rp-cAMPS) or protein kinase A inhibitor (H7 or H89) was added to PC12 cells prior to BPA-treatment. All of these agents suppressed BPA-evoked dopamine release, indicating that multiple signaling pathways may be involved in BPA-evoked dopamine release in PC12 cells. In conclusion, we demonstrated that BPA induced dopamine release in a non-genomic manner through guanine nucleotide-binding protein and N-type calcium channels. These findings illustrate a novel function of BPA and suggest that exposure to BPA influences the function of dopaminergic neurons.
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PMID:Non-genomic modulation of dopamine release by bisphenol-A in PC12 cells. 1471 5

Cardiac Ca(2+) transients are enhanced by cAMP-dependent protein kinase (PKA). However, PKA-dependent modulation of ryanodine receptor (RyR) function in intact cells is difficult to measure, because PKA simultaneously increases Ca(2+) current (I(Ca)), SR Ca(2+) uptake and SR Ca(2+) loading (which independently increase SR Ca(2+) release). We measured I(Ca) and SR Ca(2+) release +/- 1 microm isoproterenol (ISO; isoprenaline) in voltage-clamped ventricular myocytes of rabbits and transgenic mice (expressing only non-phosphorylatable phospholamban). This mouse model helps control for any effect of ISO-enhanced SR uptake on observed release, but the two species produced essentially identical results. SR Ca(2+) load and I(Ca) were adjusted by conditioning. We thus evaluated PKA effects on SR Ca(2+) release at constant SR Ca(2+) load and I(Ca) trigger (with constant unitary I(Ca)). The amount of SR Ca(2+) release increased as a function of either I(Ca) or SR Ca(2+) load, but ISO did not alter the relationships (measured as gain or fractional release). This was true over a wide range of SR Ca(2+) load and I(Ca). However, the maximal rate of SR Ca(2+) release was approximately 50% faster with ISO (at most loads and I(Ca) levels). We conclude that the isolated effect of PKA on SR Ca(2+) release is an increase in maximal rate of release and faster turn-off of release (such that integrated SR Ca(2+) release is unchanged). The increased amount of SR Ca(2+) release normally seen with ISO depends primarily on increased I(Ca) trigger and SR Ca(2+) load, whereas faster release kinetics may be the main result of RyR phosphorylation.
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PMID:Modulation of excitation-contraction coupling by isoproterenol in cardiomyocytes with controlled SR Ca2+ load and Ca2+ current trigger. 1472 5

The cardiac ryanodine receptor (RyR2)/calcium release channel on the sarcoplasmic reticulum is required for muscle excitation-contraction coupling. Using site-directed mutagenesis, we identified the specific Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation site on recombinant RyR2, distinct from the site for protein kinase A (PKA) that mediates the "fight-or-flight" stress response. CaMKII phosphorylation increased RyR2 Ca2+ sensitivity and open probability. CaMKII was activated at increased heart rates, which may contribute to enhanced Ca2+-induced Ca2+ release. Moreover, rate-dependent CaMKII phosphorylation of RyR2 was defective in heart failure. CaMKII-mediated phosphorylation of RyR2 may contribute to the enhanced contractility observed at higher heart rates. The full text of this article is available online at http://circres.ahajournals.org.
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PMID:Ca2+/calmodulin-dependent protein kinase II phosphorylation regulates the cardiac ryanodine receptor. 1501 28

Signal transduction networks coordinate a wide variety of cellular functions, including gene expression, metabolism, and cell fate processes. Understanding biological networks quantitatively is a major challenge to post-genomic biology, and mechanistic systems models will be crucial for this task. Here, we review approaches towards developing mechanistic systems models of established cell signaling networks. The ability of mechanistic system models to generate testable biological hypotheses and experimental strategies is discussed. As a case study of model development and analysis, we examined the functional roles of phospholamban, the L-type calcium channel, the ryanodine receptor, and troponin I phosphorylation upon beta-adrenergic stimulation in the rat ventricular myocyte. Model analysis revealed that while protein kinase A-mediated phosphorylation of the ryanodine receptor greatly increases its calcium sensitivity, calcium autoregulation may adapt quickly by negating potential increases in contractility. Systematic combinations of in silico perturbations supported the conclusion that phospholamban phosphoregulation is the primary mechanism for increased sarcoplasmic reticulum load and calcium relaxation rate during beta-adrenergic stimulation, while both phospholamban and the L-type calcium channel contribute to increased systolic calcium. Combined with detailed experimental studies, mechanistic systems models will be valuable for developing a quantitative understanding of cell signaling networks.
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PMID:Mechanistic systems models of cell signaling networks: a case study of myocyte adrenergic regulation. 1514 47

Heart failure remains a leading cause of mortality in the Western world. An important hallmark of heart failure is reduced myocardial contractility. Alterations in intracellular Ca2+ handling play a major role in the pathophysiology of these contractile abnormalities. Several defects in the excitation-contraction (EC) coupling system have been identified in patients with heart failure. Alterations in the density and function of proteins relevant for EC coupling have been reported. Chronic stimulation of the beta-adrenergic signaling pathway leads to protein kinase A (PKA) hyperphosphorylation of the cardiac ryanodine receptor (RyR2), which dissociates FKBP12.6 from RyR2, thereby altering channel gating and promoting diastolic sarcoplasmic reticulum (SR) Ca2+ release. This may deplete the SR Ca2+ stores, which may reduce myocardial contractility. Clinical studies have demonstrated that beta-adrenergic receptor blockers reduce morbidity and mortality in all grades of congestive heart failure. Our experimental data indicate that beta-blockers reverse RyR2 hyperphosphorylation and normalize channel gating, which is associated with increased contractility in heart failure. In conclusion, chronic hyperactivity of the beta-adrenergic signaling pathway impairs intracellular Ca2+ handling, which leads to reduced contractility in patients with heart failure.
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PMID:Molecular determinants of altered contractility in heart failure. 1517 27

The cardiac ryanodine receptor (RyR) is the sarcoplasmic reticulum (SR) Ca-release channel which is centrally involved in the myocyte excitation-contraction (E-C) coupling process and certain cardiac arrhythmias, and even contributes to pacemaker activity in the heart. The RyR is also the center of a massive macromolecular complex which includes numerous regulatory proteins which can modulate RyR function. This complex includes proteins that interact with the cytoplasmic part of the RyR directly or indirectly (e.g. calmodulin (CaM), FK-506-binding proteins, protein kinase A, Ca-CaM-dependent protein kinase, phosphatases 1 and 2A, mAKAP, spinophilin, PR130, sorcin, triadin, junctin, calsequestrin and Homer). Information is evolving in terms of understanding both the physical/molecular nature of the protein-protein interactions between RyR and these other proteins. There is also a slowly developing picture as to how this complex of proteins may be involved in the functional modulation of the RyR. This RyR complex exists in physical proximity to regulatory complexes associated with sarcolemmal Ca channels, which have some similar components. These complexes, and their relative independence emphasizes the importance of thinking about other aspects of very local molecular signaling, analogous to the local control of SR Ca-release at the heart of current (E-C) coupling theory.
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PMID:Macromolecular complexes regulating cardiac ryanodine receptor function. 1527 12

Altered cardiac ryanodine receptor (RyR2) function has an important role in heart failure and genetic forms of arrhythmias. RyR2 constitutes the major intracellular Ca2+ release channel in the cardiac sarcoplasmic reticulum (SR). The peptidyl-prolyl isomerase calstabin2 (FKBP12.6) is a component of the RyR2 macromolecular signaling complex. Calstabin2 binding to RyR2 is regulated by PKA phosphorylation of Ser2809 in RyR2. PKA phosphorylation of RyR2 decreases the binding affinity for calstabin2 and increases RyR2 open probability and sensitivity to Ca2+-dependent activation. In heart failure, a majority of studies have found that RyR2 becomes chronically PKA hyper-phosphorylated which depletes calstabin2 from the channel complex. Calstabin2 dissociation causes a diastolic SR Ca2+ leak contributing to depressed intracellular Ca2+ cycling and decreased cardiac contractility. Missense mutations linked to genetic forms of exercise-induced arrhythmias and sudden cardiac death also cause decreased calstabin2-binding affinity and leaky RyR2 channels. We review the importance of calstabin2 for RyR2 function and excitation-contraction coupling, and discuss new observations that implicate dysregulation of calstabin2 binding as a central mechanism for abnormal calcium cycling in heart failure and triggered arrhythmias.
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PMID:Calstabin deficiency, ryanodine receptors, and sudden cardiac death. 1533 74

Agrin has been implicated in multiple aspects of central nervous system (CNS) neuron differentiation and function including neurite formation, synaptogenesis, and synaptic transmission. However, little is known about the signaling mechanisms whereby agrin exerts its effects. We have recently identified a neuronal receptor for agrin, whose activation induces expression of c-fos, and provided evidence that agrin binding to this receptor is associated with a rise in intracellular Ca2+, a ubiquitous second messenger capable of mediating a wide range of effects. To gain further insight into agrin's role in brain, we used Ca2+ imaging to explore agrin signal transduction in cultured cortical neurons. Bath application of either z+ or z-agrin isoforms resulted in marked changes in intracellular Ca2+ concentration specifically in neurons. Propagation of the Ca2+ response was a two-step process characterized by an initial increase in intracellular Ca2+ mediated by ryanodine receptor (RyR) release from intracellular stores, supplemented by influx through voltage-gated calcium channels (VGCCs). Agrin-induced increases in intracellular Ca2+ were blocked by genistein and herbimycin, suggesting that the agrin receptor is a tyrosine kinase. Ca2+ release from intracellular stores activates both calcium/calmodulin-dependent kinase II (CaMKII) and mitogen activated protein kinase (MAPK). Activation of CaMKII is required for propagation of the Ca2+ wave itself, whereas both MAPK and CaMKII play a role in mediating long latency responses such as induction of c-fos. These results suggest that an agrin-dependent tyrosine kinase could play a critical role in modulating levels of intracellular Ca2+ and activity of MAPK and CaMKII in CNS neurons.
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PMID:Agrin signaling in cortical neurons is mediated by a tyrosine kinase-dependent increase in intracellular Ca2+ that engages both CaMKII and MAPK signal pathways. 1538 2


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