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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Sarcolipin (SLN) is a small molecular weight sarcoplasmic reticulum (SR) membrane protein expressed both in cardiac and skeletal muscle tissues. Recent studies using transgenic mouse models have demonstrated that SLN is an important regulator of cardiac SR Ca2+ ATPase 2a (SERCA2a). However, there is a paucity of information regarding the SLN protein expression in small versus larger mammals and its regulation during development and cardiac pathophysiology. Therefore, the major goal of this study was to generate an SLN specific antibody and perform detailed analyses of SLN protein expression during muscle development and in the diseased myocardium. The important findings of the present study are: (i) in small mammals, SLN expression is predominant in the atria but low in the ventricle and in skeletal muscle tissues, whereas in large mammals, SLN is quite abundant in skeletal muscle tissues than the atria, (ii) SLN and SERCA2a are co-expressed in all striated muscle tissues studied except ventricle and co-ordinately regulated during muscle development and (iii) SLN protein levels are approximately 3 fold upregulated in the atria of heart failure dogs and approximately 30% decreased in the atria of hearts prone to myocardial ischemia. In addition we found that in the phospholamban null atria, SLN protein levels are upregulated.
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PMID:Differential expression of sarcolipin protein during muscle development and cardiac pathophysiology. 1756 Nov 7

Sarcolipin was incorporated into a lipid bilayer anchored to a mercury electrode through a hydrophilic tetraethyleneoxy chain. The behavior of this tethered bilayer lipid membrane incorporating sarcolipin was investigated by electrochemical impedance spectroscopy and by recording charge versus time curves after potential jumps. When the transmembrane potential starts to become negative on the trans side, evidence is provided that sarcolipin aggregates into ion-conducting pores. Over the range of physiological transmembrane potentials, these pores are permeable to small inorganic anions such as chloride, phosphate, or sulfate but impermeable to inorganic cations such as Na+ and K+. Only at transmembrane potentials more negative than approximately -150 mV on the trans side do sarcolipin channels allow the translocation of the latter cations. A tentative relationship between this property of sarcolipin and its regulatory function on Ca-ATPase of sarcoplasmic reticulum is proposed.
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PMID:An electrochemical investigation of sarcolipin reconstituted into a mercury-supported lipid bilayer. 1758 75

The transmembrane protein sarcolipin regulates calcium storage in the sarcoplasmic reticulum of skeletal and cardiac muscle cells by modulating the activity of sarco(endo)plasmic reticulum Ca(2+)-ATPases (SERCAs). The highly conserved C-terminal region ((27)RSYQY-COOH) of sarcolipin helps to target the protein to the sarcoplasmic reticulum membrane and may also participate in the regulatory interaction between sarcolipin and SERCA. Here we used solid-state NMR measurements of local protein dynamics to illuminate the direct interaction between the Tyr(29) and Tyr(31) side groups of sarcolipin and skeletal muscle Ca(2+)-ATPase (SERCA1a) embedded in dioleoylphosphatidylcholine bilayers. Further solid-state NMR experiments together with functional measurements on SERCA1a in the presence of NAc-RSYQY, a peptide representing the conserved region of sarcolipin, suggest that the peptide binds to the same site as the parent protein at the luminal face of SERCA1a, where it reduces V(max) for calcium transport and inhibits ATP hydrolysis with an IC(50) of approximately 200 microM. The inhibitory effect of NAc-RSYQY is remarkably sequence-specific, with the native aromatic residues being essential for optimal inhibitory activity. This combination of physical and functional measurements highlights the importance of aromatic and polar residues in the C-terminal region of sarcolipin for regulating calcium cycling and muscle contractility.
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PMID:Solid-state NMR and functional measurements indicate that the conserved tyrosine residues of sarcolipin are involved directly in the inhibition of SERCA1. 1761 28

Sarcolipin is a novel regulator of cardiac sarcoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) and is expressed abundantly in atria. In this study we investigated the physiological significance of sarcolipin in the heart by generating a mouse model deficient for sarcolipin. The sarcolipin-null mice do not show any developmental abnormalities or any cardiac pathology. The absence of sarcolipin does not modify the expression level of other Ca2+ handling proteins, in particular phospholamban, and its phosphorylation status. Calcium uptake studies revealed that, in the atria, ablation of sarcolipin resulted in an increase in the affinity of the SERCA pump for Ca2+ and the maximum velocity of Ca2+ uptake rates. An important finding is that ablation of sarcolipin resulted in an increase in atrial Ca2+ transient amplitudes, and this resulted in enhanced atrial contractility. Furthermore, atria from sarcolipin-null mice showed a blunted response to isoproterenol stimulation, implicating sarcolipin as a mediator of beta-adrenergic responses in atria. Our study documented that sarcolipin is a key regulator of SERCA2a in atria. Importantly, our data demonstrate the existence of distinct modulators for the SERCA pump in the atria and ventricles.
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PMID:Ablation of sarcolipin enhances sarcoplasmic reticulum calcium transport and atrial contractility. 1797 38

Cardiac sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA2a) plays a central role in myocardial contractility. SERCA2a actively transports Ca(2+) into the SR and regulates cytosolic Ca(2+) concentration, SR Ca(2+) load, and the rate of contraction and relaxation of the heart. In the heart, SERCA pump activity is regulated by two small molecular weight proteins: phospholamban (PLB) and sarcolipin (SLN). Decreases in the expression levels of SERCA2a have been observed in a variety of pathological conditions. In addition, altered expression of PLB and SLN has been reported in many cardiac diseases. Thus, SERCA2a is a major regulator of intracellular Ca(2+) homeostasis, and changes in the expression and activity of the SERCA pump contribute to the decreased SR Ca(2+) content and cardiac dysfunction during pathogenesis. In this review, we discuss the mechanisms controlling SERCA pump expression and activity both during normal physiology and under pathological states.
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PMID:Regulation of sarcoplasmic reticulum Ca2+ ATPase pump expression and its relevance to cardiac muscle physiology and pathology. 1800 43

A robust cross-link between Gln(23) in phospholamban (PLN) and Lys(328) in the sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA1a) is formed in the presence or absence of oxidant and is susceptible to both PLN phosphorylation and SERCA1a Ca(2+) binding. This cross-link provides precisely the evidence needed to support our earlier proposal that collision of the PLN transmembrane helix at Asn(27) with the cytosolic extension of M4 at Leu(321) leads to unwinding of the helix. In a study of site-specific interactions among PLN, sarcolipin (SLN), and SERCA1a, we determined that mutations of some specific amino acids in PLN or SLN diminish either the super-inhibition imposed on SERCA1a function by the PLN-SLN binary complex or the physical interactions between PLN and SLN or both. These results have led to a revision of our earlier model for the PLN-SLN-SERCA1a complex.
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PMID:Interaction sites among phospholamban, sarcolipin, and the sarco(endo)plasmic reticulum Ca(2+)-ATPase. 1805 95

Previous work suggested that altered Ca(2+) homeostasis might contribute to dysfunction of nebulin-free muscle, as gene expression analysis revealed that the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)-inhibitor sarcolipin (SLN) is up-regulated >70-fold in nebulin knockout mice, and here we tested this proposal. We investigated SLN protein expression in nebulin-free and wild-type skeletal muscle, as well as expression of other Ca(2+)-handling proteins. Ca(2+) uptake capacity was determined in isolated sarcoplasmic reticulum vesicles and in intact myofibers by measuring Ca(2+) transients. Muscle contractile performance was determined in skinned muscle activated with exogenous Ca(2+), as well as in electrically stimulated intact muscle. We found profound up-regulation of SLN protein in nebulin-free skeletal muscle, whereas expression of other Ca(2+)-handling proteins was not (calsequestrin and phospholamban) or was minimally (SERCA) affected. Speed of Ca(2+) uptake was >3-fold decreased in sarcoplasmic reticulum vesicles isolated from nebulin-free muscle as well as in nebulin-free intact myofibers. Ca(2+)-activated stress in skinned muscle and stress produced by intact nebulin-free muscle were reduced to a similar extent compared with wild type. Half-relaxation time was significantly longer in nebulin-free compared with wild-type muscle. Thus, the present study demonstrates for the first time that nebulin might also be involved in physiological Ca(2+) handling of the SR-myofibrillar system.
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PMID:Sarcoplasmic reticulum calcium uptake and speed of relaxation are depressed in nebulin-free skeletal muscle. 1843 34

Following pulmonary artery banding (PAB), the contractile function of right ventricle diminishes over time. Subsequently, the right atrium (RA) has to contract against a higher afterload, but it is unknown to what extent ventricular dysfunction has an effect on the atrial contractility. We hypothesized that right ventricular pressure overload may have an affect on atrial contractility and Ca(2+) transport protein expression. Therefore, we induced pressure overload of the right ventricle by PAB for 10 wk in rabbits and examined the changes in the expression of Ca(2+) transport proteins in the atrium. We demonstrate that PAB significantly decreased the expression of sarco(endo)plasmic reticulum Ca(2+)-ATPase (Serca) 2a while expression of Na(+)/Ca(2+) exchanger-1 was significantly upregulated in the RA but not in the left atria of rabbit hearts, indicating that pressure is the major trigger. A decrease in Serca2a expression was concomitant with a significant decrease in sarcolipin (SLN), possibly indicating a compensatory role of SLN. The decreased expression of SLN was unable to completely restore sarcoplasmic reticulum Ca(2+) uptake function of Serca2a. Functional contractile assessments in isolated trabeculae showed no difference between PAB- and sham-operated rabbits at 1 Hz but displayed an enhanced force development at higher frequencies and in the presence of isoproterenol, while twitch timing was unaffected. Our results indicate that right ventricular mechanical overload due to PAB affects the expression of the Ca(2+)-handling proteins in the RA in rabbits.
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PMID:Pulmonary artery banding alters the expression of Ca2+ transport proteins in the right atrium in rabbits. 1937 11

We report molecular dynamics simulations in the explicit membrane environment of a small membrane-embedded protein, sarcolipin, which regulates the sarcoplasmic reticulum Ca-ATPase activity in both cardiac and skeletal muscle. In its monomeric form, we found that sarcolipin adopts a helical conformation, with a computed average tilt angle of 28 +/- 6 degrees and azymuthal angles of 66 +/- 22 degrees, in reasonable accord with angles determined experimentally (23 +/- 2 degrees and 50 +/- 4 degrees, respectively) using solid-state NMR with separated-local-field experiments. The effects of time and spatial averaging on both (15)N chemical shift anisotropy and (1)H/(15)N dipolar couplings have been analyzed using short-time averages of fast amide out-of-plane motions and following principal component dynamic trajectories. We found that it is possible to reproduce the regular oscillatory patterns observed for the anisotropic NMR parameters (i.e., PISA wheels) employing average amide vectors. This work highlights the role of molecular dynamics simulations as a tool for the analysis and interpretation of solid-state NMR data.
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PMID:Tilt and azimuthal angles of a transmembrane peptide: a comparison between molecular dynamics calculations and solid-state NMR data of sarcolipin in lipid membranes. 1941 70


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