Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both the cardiac action potential duration (APD) (0.6-1 s) and resting heart rate (30-40 beats/min) in the horse are significantly different from humans and smaller mammals, including the rabbit. This would be anticipated to have consequences for excitation-contraction (EC) coupling and require adaptation of the individual processes involved. The sarcoplasmic reticulum (SR) is one of the main components involved in EC coupling. This study examines and compares the activity of this organelle in the horse with that of the rabbit. In particular, the study focuses on SR Ca2+ release via the Ca2+ release channel/ryanodine receptor (RyR2) and Ca2+ uptake via the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) pump. Isolated cardiomyocytes from both horse and rabbit hearts were permeabilized, bathed in a mock intracellular solution, and exposed to a specified [Ca2+]. Rabbit cardiomyocytes exposed to 260 nM [Ca2+] produced spontaneous Ca2+ release and propagated Ca2+ waves. Horse cells failed to produce Ca2+ waves; instead, only local release in the form of Ca2+ sparks was evident. However, at 550 nM [Ca2+], Ca2+ waves were produced in both species. Ca2+ waves were four times less frequent yet approximately 1.5 times greater in amplitude in the horse compared with the rabbit. Ca2+ wave velocity was comparable between the species. The reason for this disparity in Ca2+ wave characteristics is unknown. Separate measurements of oxalate-supported Ca2+ uptake into the SR suggest that both horse and rabbit cardiomyocytes have comparable levels SERCA activity. The possible reasons for the observed differences in SR Ca2+ release between the horse and rabbit are discussed.
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PMID:Comparison of Ca2+ release and uptake characteristics of the sarcoplasmic reticulum in isolated horse and rabbit cardiomyocytes. 1511 16

The contribution of Ca(2+) release from intracellular stores to the rise in the free cytosolic Ca(2+) concentration ([Ca(2+)](c)) triggered by Ca(2+) influx was investigated in mouse pancreatic beta-cells. Depolarization of beta-cells by 45 mm K(+) (in the presence of 15 mm glucose and 0.1 mm diazoxide) evoked two types of [Ca(2+)](c) responses: a monotonic and sustained elevation; or a sustained elevation superimposed by a transient [Ca(2+)](c) peak (TCP) (40-120 s after the onset of depolarization). Simultaneous measurements of [Ca(2+)](c) and voltage-dependent Ca(2+) current established that the TCP did not result from a larger Ca(2+) current. Abolition of the TCP by thapsigargin and its absence in sarco-endoplasmic reticulum Ca(2+)-ATPase 3 (SERCA3) knockout mice show that it is caused by Ca(2+) mobilization from the endoplasmic reticulum. A TCP could not be evoked by the sole depolarization of beta-cells but required a rise in [Ca(2+)](c) pointing to a Ca(2+)-induced Ca(2+) release (CICR). This CICR did not involve inositol 1,4,5-trisphosphate (IP(3)) receptors (IP(3)Rs) because it was resistant to heparin. Nor did it involve ryanodine receptors (RyRs) because it persisted after blockade of RyRs with ryanodine, and was not mimicked by caffeine, a RyR agonist. Moreover, RyR1 and RyR2 mRNA were not found and RyR3 mRNA was only slightly expressed in purified beta-cells. A CICR could also be detected in a limited number of cells in response to glucose. Our data demonstrate, for the first time in living cells, the existence of an atypical CICR that is independent from the IP(3)R and the RyR. This CICR is prominent in response to a supraphysiological stimulation with high K(+), but plays little role in response to glucose in non-obese mouse pancreatic beta-cells.
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PMID:Atypical Ca2+-induced Ca2+ release from a sarco-endoplasmic reticulum Ca2+-ATPase 3-dependent Ca2+ pool in mouse pancreatic beta-cells. 1521 77

Both cardiac and skeletal muscle ryanodine receptors (RyRs) are parts of large complexes that include a number of kinases and phosphatases. These RyRs have several potential phosphorylation sites in their cytoplasmic domains, but the functional consequences of phosphorylation and the identity of the enzymes responsible have been subjects of considerable controversy. Hyperphosphorylation of Ser-2809 in RyR2 (cardiac isoform) and Ser-2843 in RyR1 (skeletal isoform) has been suggested to cause the dissociation of the FK506-binding protein (FKBP) from RyRs, producing "leaky channels," but some laboratories find no relationship between phosphorylation and FKBP binding. Also debated is the identity of the kinases that phosphorylate these serines: cAMP-dependent protein kinase (PKA) versus calmodulin kinase II (CaMKII). Phosphorylation of other targets of these kinases could also alter calcium homeostasis. For example, PKA also phosphorylates phospholamban (PLB), altering the Sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) activity. This review summarizes the major findings and controversies associated with phosphorylation of RyRs.
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PMID:Phosphorylation of ryanodine receptors. 1570 78

Sorcin is a 21.6-kDa Ca(2+) binding protein of the penta-EF hand family. Several studies have shown that sorcin modulates multiple proteins involved in excitation-contraction (E-C) coupling in the heart, such as the cardiac ryanodine receptor (RyR2), L-type Ca(2+) channel, and Na(+)-Ca(2+) exchanger, while it has also been shown to be phosphorylated by cAMP-dependent protein kinase (PKA). To elucidate the effects of sorcin and its PKA-dependent regulation on E-C coupling in the heart, we identified the PKA-phosphorylation site of sorcin, and found that serine178 was preferentially phosphorylated by PKA and dephosphorylated by protein phosphatase-1. Isoproterenol allowed sorcin to translocate to the sarcoplasmic reticulum (SR). In addition, adenovirus-mediated overexpression of sorcin in adult rat cardiomyocytes significantly increased both the rate of decay of the Ca(2+) transient and the SR Ca(2+) load. An assay of oxalate-facilitated Ca(2+) uptake showed that recombinant sorcin increased Ca(2+) uptake in a dose-dependent manner. These data suggest that sorcin activates the Ca(2+)-uptake function in the SR. In UM-X7. 1 cardiomyopathic hamster hearts, the relative amount of sorcin was significantly increased in the SR fraction, whereas it was significantly decreased in whole-heart homogenates. In failing hearts, PKA-phosphorylated sorcin was markedly increased, as assessed using a back-phosphorylation assay with immunoprecipitated sorcin. Our results suggest that sorcin activates Ca(2+)-ATPase-mediated Ca(2+) uptake and restores SR Ca(2+) content, and may play critical roles in compensatory mechanisms in both Ca(2+) homeostasis and cardiac dysfunction in failing hearts.
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PMID:Sorcin interacts with sarcoplasmic reticulum Ca(2+)-ATPase and modulates excitation-contraction coupling in the heart. 1575 88

The effect of S100A1 protein on cardiac excitation-contraction (E-C) coupling was studied using recombinant human S100A1 protein (0.01-10 microM) introduced into single rabbit ventricular cardiomyocytes via a patch pipette. Voltage clamp experiments (20 degrees C) indicated that 0.1 microM S100A1 increased Ca(2+) transient amplitude by approximately 41% but higher or lower S100A1 concentrations had no significant effect. L-type Ca(2+) current amplitude or Ca(2+) efflux rates via the Na(+)/Ca(2+) exchanger (NCX) were unaffected. The rate of Ca(2+) uptake associated with the SR Ca(2+)-ATPase (SERCA2a) was increased by approximately 22% with 0.1 microM S100A1, but not at other S100A1 concentrations. Based on the intracellular Ca(2+) and I(NCX) signals in response to 10 mM caffeine, no significant change in SR Ca(2+) content was observed with S100A1 (0.01-10 microM). Therefore, 0.1 microM S100A1 appeared to increase the fractional Ca(2+) release from the SR. This result was confirmed by measurements of Ca(2+) transient amplitude at a range of SR Ca(2+) contents. The hyperbolic relationship between these two parameters was shifted to the left by 0.1 microM S100A1. [(3)H]-ryanodine binding studies indicated that S100A1 increased ryanodine receptor (RyR) activity at 0.1 and 0.3 microM Ca(2). As with the effects on E-C coupling, 0.1 microM S100A1 produced the largest effect. Co-immunoprecipitation studies on a range of Ca(2+)-handling proteins support the selective interaction of S100A1 on SERCA2a and RyR. In summary, S100A1 had a stimulatory action on RyR2 and SERCA2a in rabbit cardiomyocytes. Under the conditions of this study, the net effect of this dual action is to enhance the Ca(2+) transient amplitude without significantly affecting the SR Ca(2+) content.
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PMID:S100A1 increases the gain of excitation-contraction coupling in isolated rabbit ventricular cardiomyocytes. 1623 9

The Ca(2+) antagonists nifedipine has been used for more than three decades to treat hypertension, but its effects on the transcriptional regulation of cardiac genes are basically unknown. We therefore studied expression of genes coding for ion channels, ion transporters and associated partners as well as Ca(2+)-binding proteins in ventricular tissue of normotensive and spontaneously hypertensive (SH) rats after repeated intraperitoneally (i.p.) dosing of nifedipine. Notably, we observed significant (P < 0.05) repression in transcript levels of most of the genes investigated, including cardiac Na(+), K(+), Ca(2+)-channels (L-type Ca(2+)-channel, K(ir)3.4, K(ir)6.1, Na(v)1.5), ATP-driven ion exchangers (Na(+)-K(+)-ATPase, NCX-1, PMCA 2 and 4, SERCA 2a and 2b) and their associated partners (phospholamban, RyR-2) as well as cytoskeletal proteins (alpha and beta-MHC, alpha cardiac and alpha skeletal actin, troponin T and I). Repression in transcript levels was, however, only seen in ventricular tissue of hypertensive animals. This points to fundamental differences in the mode of action of nifedipine in diseased and healthy animals. Indeed, this preponderance of repressed genes will promote disturbed ion homeostasis to result in contractile dysfunction. It is of considerable importance that repressed gene expression was also seen in end-stage human heart failure. We propose repression of cardiac-specific gene expression as a hallmark of nifedipine treatment in hypertrophic hearts.
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PMID:Nifedipine represses ion channels, transporters and Ca(2+)-binding proteins in hearts of spontaneously hypertensive rats. 1634 76

Periodic changes in calcium (Ca(2+)) concentration in cardiomyocytes are essential for cardiac contraction and relaxation, and the intracellular Ca(2+)concentration is integrally regulated by proteins associated with the sarcoplasmic reticulum (SR), an extensive intracellular membrane system. The activity of the cardiac ryanodine receptor (RyR2) and the sarco/endoplasmic reticulum Ca(2+) ATPase 2a (SERCA2a) are known to be under fine-tuning by their intrinsic regulatory domains and associated SR proteins. A growing body of evidence, including studies using genetically engineered mouse models, has shown that Ca(2+)cycling and Ca(2+)-dependent signaling pathways play a pivotal role in heart failure. The improvement of the SR function has ameliorated effects on cardiac pump function and it has potential therapeutic value for heart failure.
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PMID:[Sarcoplasmic reticulum function and heart failure: a novel therapeutic target for heart failure]. 1639 49

Both beta-adrenergic blockade and bradycardia may contribute to the therapeutic effect of beta-blockers in chronic heart failure (CHF). This study tested the relative importance of bradycardia by comparing cilobradine (Cilo), a sinus node inhibitor, with a beta-blocker, metoprolol (Meto), in an established canine model of CHF. Dogs were chronically instrumented for hemodynamic and left ventricular (LV) volume measurements. CHF was created by daily coronary embolization via a chronically implanted coronary (left anterior descending coronary artery) catheter. After establishment of CHF, control (n=6), Meto (30 mg/day, n=5), Cilo (low) (1 mg/kg/day, n=5), or Cilo (high) (3 mg/kg/day, n=5) was given orally for 12 weeks. Systemic hemodynamics, echocardiography, and pressure volume analysis were measured at baseline, at CHF, and 3 months after treatment in an awake state. Protein levels of cardiac sarcoplasmic reticulum calcium-ATPase (SERCA2a), ryanodine receptor (RyR2), and Na+-Ca2+ exchanger (NCX1) were measured by Western blot. RyR2 protein kinase A (PKA) phosphorylation was determined by back-phosphorylation. After 12 weeks, Meto and Cilo (high and low) produced similar bradycardic effects, accompanied by a significantly improved LV dP/dt versus control [Meto, 2602+/-70; Cilo (low), 2517+/-45; Cilo (high), 2579+/-78; control, 1922+/-115 mm Hg/s; p<0.05]. Both Meto and Cilo (high) normalized protein levels of SERCA2a and NCX1 and reversed PKA hyperphosphorylation of RyR2, in contrast to controls. High-dose cilobradine effectively produced bradycardia and improved cardiac function after CHF, comparable with metoprolol. Restored protein levels of SERCA2a and improved function of RyR2 may be important mechanisms associated with cilobradine therapy.
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PMID:Bradycardic therapy improves left ventricular function and remodeling in dogs with coronary embolization-induced chronic heart failure. 1727 96

The various cardiac regions have specific action potential properties appropriate to their electrical specialization, resulting from a specific pattern of ion-channel functional expression. The present study addressed regionally defined differential ion-channel expression in the non-diseased human heart with a genomic approach. High-throughput real-time RT-PCR was used to quantify the expression patterns of 79 ion-channel subunit transcripts and related genes in atria, ventricular epicardium and endocardium, and Purkinje fibres isolated from 15 non-diseased human donor hearts. Two-way non-directed hierarchical clustering separated atria, Purkinje fibre and ventricular compartments, but did not show specific patterns for epicardium versus endocardium, nor left- versus right-sided chambers. Genes that characterized the atria (versus ventricles) included Cx40, Kv1.5 and Kir3.1 as expected, but also Cav1.3, Cav3.1, Cav alpha2 delta2, Nav beta1, TWIK1, TASK1 and HCN4. Only Kir2.1, RyR2, phospholamban and Kv1.4 showed higher expression in the ventricles. The Purkinje fibre expression-portrait (versus ventricle) included stronger expression of Cx40, Kv4.3, Kir3.1, TWIK1, HCN4, ClC6 and CALM1, along with weaker expression of mRNA encoding Cx43, Kir2.1, KChIP2, the pumps/exchangers Na(+),K(+)-ATPase, NCX1, SERCA2, and the Ca(2+)-handling proteins RYR2 and CASQ2. Transcripts that were more strongly expressed in epicardium (versus endocardium) included Cav1.2, KChIP2, SERCA2, CALM3 and calcineurin-alpha. Nav1.5 and Nav beta1 were more strongly expressed in the endocardium. For selected genes, RT-PCR data were confirmed at the protein level. This is the first report of the global portrait of regional ion-channel subunit-gene expression in the non-diseased human heart. Our data point to significant regionally determined ion-channel expression differences, with potentially important implications for understanding regional electrophysiology, arrhythmia mechanisms, and responses to ion-channel blocking drugs. Concordance with previous functional studies suggests that regional regulation of cardiac ion-current expression may be primarily transcriptional.
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PMID:Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart. 1754 Jun 96

In animal models of conotruncal heart defects, an abnormal calcium sensitivity of the contractile apparatus and a depressed L-type calcium current have been described. Sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA) is a membrane protein that catalyzes the ATP-dependent transport of Ca(2+) from the cytosol to the SR. The activity of SERCA is inhibited by phospholamban (PLN) and sarcolipin (SLN), and all these proteins participate in maintaining the normal intracellular calcium handling. Ryanodine receptors (RyRs) are the major SR calcium-release channels required for excitation-contraction coupling in skeletal and cardiac muscle. Our objective was to evaluate SERCA2a (i.e., the SERCA cardiac isoform), PLN, SLN, and RyR2 (i.e., the RyR isoform enriched in the heart) gene expression in myocardial tissue of patients affected by tetralogy of Fallot (TOF), a conotruncal heart defect. The gene expression of target genes was assessed semiquantitatively by RT-PCR using the calsequestrin (CASQ, a housekeeping gene) RNA as internal standard in the atrial myocardium of 23 pediatric patients undergoing surgical correction of TOF, in 10 age-matched patients with ventricular septal defect (VSD) and in 13 age-matched children with atrial septal defect (ASD). We observed a significantly lower expression of PLN and SLN in TOF patients, while there was no difference between the expression of SERCA2a and RyR2 in TOF and VSD. These data suggest a complex mechanism aimed to enhance the intracellular Ca(2+) reserve in children affected by tetralogy of Fallot.
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PMID:SERCA2a, phospholamban, sarcolipin, and ryanodine receptors gene expression in children with congenital heart defects. 1751 62


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