Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although primary genetic defects have been identified for some forms of inherited cardiomyopathy, it is not well understood how secondary abnormalities actually lead to muscle cell destruction. Since cardiomyopathies significantly influence morbidity and mortality rates world-wide, it is important to improve the differential diagnosis of these disorders and develop potential treatments for inherited diseases of the heart. Elucidation of the secondary molecular mechanisms underlying cardiac cell necrosis might help linking a specific mutation in a cardiac gene to acute heart failure. As disturbed Ca2+-homeostasis may contribute to heart failure, we have investigated the relative abundance and oligomeric status of the sarcoplasmic reticulum Ca2+-ATPase and phospholamban in various cardiomyopathies. These two proteins represent important factors in cardiac relaxation. The SERCA2 isoform of the Ca2+-ATPase represents a major Ca2+-removal system in cardiac muscle fibres and phospholamban is a regulator of Ca2+-pump activity. Although Ca2+-ATPase expression did not seem to be markedly altered, the comparative immunoblot analysis presented here clearly shows that phospholamban expression is increased in dilated cardiomyopathy, possibly explaining the decreased Ca2+-uptake in the disease. In contrast to the normal enzyme, the Ca2+-pump was demonstrated to exhibit an impairment of crosslinker-stabilized oligomerization in dilated cardiomyopathy. Since Ca2+-ATPase oligomerization is important for co-operative kinetics and protection against proteolytic degradation, the monomeric Ca2+-ATPase may trigger an abnormal contraction-relaxation cycle in dilated cardiomyopathy leading to heart failure.
Int J Mol Med 2000 Nov
PMID:Impaired Ca2+-ATPase oligomerization and increased phospholamban expression in dilated cardiomyopathy. 1102 19

Heart failure of diverse causes is associated with abnormalities of sarcoplasmic reticulum (SR) Ca(2+)transport. The purpose of this study was to determine whether the thyroid hormone analogue, 3,5-diiodothyropropionic acid (DITPA), prevents abnormal Ca(2+)transport and expression of SR proteins associated with post-infarction heart failure. New Zealand White rabbits were randomly assigned to circumflex artery ligation or sham operation, and to DITPA administration (3.75 mg/kg/day) or no treatment in a two-by-two factorial design. After 3 weeks, echo-Doppler and LV hemodynamic measurements were performed. From ventricular tissue, single myocyte shortening and relaxation were determined, and Ca(2+)transport was measured in homogenates and SR-enriched microsomes. Levels of mRNA and protein content were determined for the SR Ca(2+)-ATPase (SERCA2a), phospholamban (PLB), cardiac ryanodine receptor (RyR-2) and calsequestrin. The administration of DITPA improved LV contraction and relaxation and improved myocyte shortening in infarcted animals. The improvements in LV and myocyte function were associated with increases in V(max)for SR Ca(2+)transport in both homogenates and microsomes. Also, DITPA prevented the decrease in LV protein density for SERCA2a, PLB and RyR-2 post-infarction, without measurable changes in mRNA levels. The thyroid hormone analogue, DITPA, improves LV, myocyte and SR function in infarcted hearts and prevents the downregulation of SR proteins associated with post-infarction heart failure. The specific effects of DITPA on post-infarction SR Ca(2+)transport and the expression of SR proteins make this compound a potentially useful therapeutic agent for LV systolic and/or diastolic dysfunction.
J Mol Cell Cardiol 2000 Nov
PMID:Prevention of abnormal sarcoplasmic reticulum calcium transport and protein expression in post-infarction heart failure using 3, 5-diiodothyropropionic acid (DITPA). 1104 Jan

The aim of this study was to explore the possible participation of cardiac renin-angiotensin system (RAS) in the ischemia-reperfusion induced changes in heart function as well as Ca2+-handling activities and gene expression of cardiac sarcoplasmic reticulum (SR) proteins. The isolated rat hearts, treated for 10 min without and with 30 microM captopril or 100 microM losartan, were subjected to 30 min ischemia followed by reperfusion for 60 min and processed for the measurement of SR function and gene expression. Attenuated recovery of the left ventricular developed pressure (LVDP) upon reperfusion of the ischemic heart was accompanied by a marked reduction in SR Ca2+-pump ATPase, Ca2+-uptake and Ca2+-release activities. Northern blot analysis revealed that mRNA levels for SR Ca2+-handling proteins such as Ca2+-pump ATPase (SERCA2a), ryanodine receptor, calsequestrin and phospholamban were decreased in the ischemia-reperfused heart as compared with the non-ischemic control. Treatment with captopril improved the recovery of LVDP as well as SR Ca2+-pump ATPase and Ca2+-uptake activities in the postischemic hearts but had no effect on changes in Ca2+-release activity due to ischemic-reperfusion. Losartan neither affected the changes in contractile function nor modified alterations in SR Ca2+-handling activities. The ischemia-reperfusion induced decrease in mRNA levels for SR Ca2+-handling proteins were not affected by treatment with captopril or losartan. The results suggest that the improvement of cardiac function in the ischemic-reperfused heart by captopril is associated with the preservation of SR Ca2+-pump activities; however, it is unlikely that this action of captopril is mediated through the modification of cardiac RAS. Furthermore, cardiac RAS does not appear to contribute towards the ischemia-reperfusion induced changes in gene expression for SR Ca2+-handling proteins.
Mol Cell Biochem 2000 Sep
PMID:Role of cardiac renin-angiotensin system in sarcoplasmic reticulum function and gene expression in the ischemic-reperfused heart. 1110 55

The site-specific phospholamban phosphorylation was studied with respect to the interplay of cAMP- and Ca(2+)signaling in neonatal rat cardiomyocytes. To elucidate the signal pathway(s) for the activation of Ca(2+)/calmodulin-dependent protein kinase (CaMKII) we studied Thr17 phosphorylation of phospholamban in dependence of Ca(2+)channel activation by S(-)-Bay K8644 and in dependence of the depletion of the sarcoplasmic reticulum Ca(2+)stores by ryanodine or thapsigargin in the absence or presence of beta -adrenergic stimulation. The isoproterenol (0.1 microM)-induced Thr17 phosphorylation was potentiated 2.5-fold in presence of 1 microM S(-)-Bay K8644. Interestingly, S(-)-Bay K8644 alone was also able to induce Thr17 phosphorylation in a dose- and time-dependent fashion. Ryanodine (1.0 microM) reduced both the isoproterenol (0.1 microM) and S(-)-Bay K8644-(1 microM) mediated Thr17 phosphorylation by about 90%. Thapsigargin (1 microM) diminished the S(-)-Bay K8644 and isoproterenol-associated Thr17 phosphorylation by 53.5+/-6.3% and 92. 5+/-11.1%, respectively. Ser16 phosphorylation was not affected under these conditions. KN-93 reduced the Thr17 phosphorylation by S(-)-Bay K8644 and isoproterenol to levels of 1.1+/-0.3% and 8.6+/-2. 1%, respectively. However, the effect of KN-93 was attenuated (47. 8+/-3.6%) in isoproterenol prestimulated cells. Protein phosphatase inhibition by okadaic acid increased exclusively the Ser16 phosphorylation. In summary, our results reflect a cross-talk between beta -adrenoceptor stimulation and intracellular Ca(2+)at the level of CaMKII-mediated phospholamban phosphorylation in neonatal rat cardiomyocytes. We report conditions which exclusively produce Thr17 or Ser16 phosphorylation. We postulate that Ca(2+)transport systems of the sarcoplasmic reticulum are critical determinants for the activation of CaMKII that catalyzes phosphorylation of phospholamban.
J Mol Cell Cardiol 2000 Dec
PMID:Phosphorylation of phospholamban at threonine-17 in the absence and presence of beta-adrenergic stimulation in neonatal rat cardiomyocytes. 1111 93

Excitation-contraction coupling is the process by which depolarisation of the myocardial surface membrane leads to the release of Ca2+-ions from the sarcoplasmic reticulum, inducing cardiac muscle contraction. This process is made possible by an elaborate system of ion-release, uptake and sequestration that controls the contraction and relaxation cycle of heart muscle fibres. The free intracellular Ca2+-concentration determines the contractile state of the myocardium, and the sequestration of Ca2+-ions into the lumen of the sarcoplasmic reticulum by the Ca2+-ATPase pump units represents a critical step towards the maintenance of normal Ca2+-cycling. The Ca2+-ATPase pump activity is regulated by phospholamban, a small 52-amino acid protein whose phosphorylation state dictates its inhibitory action on the pump. A large body of evidence points to the central role of abnormal Ca2+-ATPase-phospholamban interactions in pathophysiological heart conditions, thereby compromising the contractile state of the cardiac muscle cell. It has been shown that alterations in the oligomeric status of the Ca2+-ATPase and modified interactions between the Ca2+-pump and its regulatory subunit phospholamban underlie the contractile dysfunction that characterises certain forms of dilated cardiomyopathy. Hence, elucidation of interactions within physiological Ca2+-ATPase pump units in normal and diseased myocardium is a vital link in the development of improved diagnostic and therapeutic techniques for dealing with this elusive condition.
Int J Mol Med 2001 Feb
PMID:Impaired Ca2+-sequestration in dilated cardiomyopathy (review). 1117 15

Myocardial inflammation contributes to the development of dilated cardiomyopathy, as well as other cardiac diseases. We have previously shown decreased left ventricular function in mice with autoimmune myocarditis. To test the hypothesis that decreased function is mediated by changes in contractility and/or Ca2+ cycling, we isolated cardiac myocytes from mice with myocarditis and age-matched controls at two time points: day 18 (prior to cardiac dysfunction) and day 35 (during cardiac dysfunction). We measured cell shortening and the Ca2+ transient simultaneously at 28 degrees C and 0.3 Hz. We also quantified proteins which regulate contractility and [Ca2+](i), using Western blot analysis. Results showed no change in cell shortening or systolic Ca2+ on day 18, despite a significant reduction in diastolic Ca2+. By day 35, the decrease in diastolic Ca2+ was accompanied by significantly reduced cell shortening and a decrease in the systolic Ca2+ transient. Protein levels of the sarcoplasmic reticulum Ca2+ ATPase were unchanged at both time points, while phospholamban and the sodium/calcium exchanger were significantly reduced in myosin-immunized mice at both time points. Calsequestrin was unchanged at day 18, but was significantly reduced in the myosin-immunized mice on day 35. Results of this study suggest that decreased diastolic Ca2+, as well as protein levels of phospholamban and the sodium/calcium exchanger, may actually contribute to disease progression in autoimmune myocarditis, while changes in calsequestrin may be related to systolic dysfunction in this model.
J Mol Cell Cardiol 2001 Mar
PMID:Changes in calcium cycling precede cardiac dysfunction during autoimmune myocarditis in mice. 1118 Oct 14

This review examines the structure and function of the sarco(endo)plasmic reticulum calcium pump (SERCA1a) in the light of the recent publication of the 2.6 A resolution structure of this protein, and looks at the increasing awareness of the key role played by SERCAs in calcium signalling. The roles played by the calcium pump isoforms, SERCA1a/b, SERCA2a/b and SERCA3a/b/c in cellular function are discussed, and the modulation of SERCA activity by phospholamban, sarcolipin and other modulatory influences is examined. The recent discoveries of human SERCA mutations leading to disease states is reviewed, and the insights into SERCA function using transgenic approaches are outlined.
Mol Membr Biol
PMID:Sarco(endo)plasmic reticulum calcium pumps: recent advances in our understanding of structure/function and biology (review). 1130 72

J. P. Slack, I. L. Grupp, R. Dash, D. Holder, A. Schmidt, M. J. Gerst, T. Tamura, C. Tilgmann, P. F. James, R. Johnson, A. M. Gerdes and E. G. Kranias. The Enhanced Contractility of the Phospholamban-deficient Mouse Heart Persists with Aging. Journal of Molecular and Cellular Cardiology (2001) 33, 1031-1040. Phospholamban ablation in the mouse is associated with significant increases in cardiac contractility. To determine whether this hyperdynamic function persists through the aging process, a longitudinal examination of age-matched phospholamban-deficient and wild-type mice was employed. Kaplan-Meier survival curves indicated no significant differences between phospholamban-deficient and wild-type mice over the first year. Examination of cardiac function revealed significant increases in the rates of contraction (+dP/dt) and relaxation (-dP/dt) in phospholamban-deficient hearts compared with their wild-type counterparts at 3, 6, 12, 18 and 24 months of age. Quantitative immunoblotting indicated that the expression levels of the sarcoplasmic reticulum Ca(2+)-ATPase were not altered in wild-type hearts, while they were significantly decreased at 12 months (40%) and 18 months (20%) in phospholamban-deficient hearts. These findings on the persistence of hyperdynamic cardiac function over the long term suggest that phospholamban may constitute an important target for treatment in heart disease.
J Mol Cell Cardiol 2001 May
PMID:The enhanced contractility of the phospholamban-deficient mouse heart persists with aging. 1134 24

The (Na+,K+)-ATPase is a plasma membrane protein complex composed of at least three subunits (alpha,beta,gamma) that couples the exchange of three cytoplasmic Na+ ions with two extracellular K+ ions, to the hydrolysis of one molecule ofATP in most animal cells. The gamma-subunit is a 66 residue membrane protein associated with the active alpha/beta binary complex. It can be considered as an archetype of single transmembrane proteins (type I) which may play a modulatory role upon association with functional membrane partners. This paper highlights similar associations observed with other ATPases such as the sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA1/SERCA 2a), but also with Cl- and/or K+ currents, ionic channels (HERG, KCNQ1) and G-protein coupled receptors (adrenomedullin, CGRP and calcitonin) which are of particular interest in the cardiovascular field. Here is reviewed the assessed or suggested regulatory role of a family of small plasma/SR associated membrane proteins including gamma-subunit, phospholemman, Mat 8, KCNE (type 1, 2 and 3), RAMP (type 1, 2 and 3), sarcolipin and phospholamban, mainly found in muscular and vascular tissues. These proteins are critical in controlling important biological processes which derive from specific associations with a binding partner and particular subcellular localizations.
Cell Mol Biol (Noisy-le-grand) 2001 Mar
PMID:The gamma-subunit of (Na+,K+)-ATPase: a representative example of human single transmembrane protein with a key regulatory role. 1135 3

Gender has recently been implicated as an important modulator of cardiovascular disease. However, it is not known how gender may specifically influence the Ca2+-handling deficits that characterize the depressed cardiac contractility of human heart failure. To elucidate the contributory role of gender to sarcoplasmic reticulum (SR) Ca2+ cycling alterations, the protein levels of SR Ca2+-ATPase (SERCA), phospholamban, and calsequestrin, as well as the site-specific phospholamban phosphorylation status, were quantified in a mixed gender population of failing (n=14) and donor (n=15) myocardia. The apparent affinity (EC50) and the maximal velocity (Vmax) of SR Ca2+-uptake were also determined to lend functional significance to any observed protein alterations. Phospholamban and calsequestrin levels were not altered; however, SERCA protein levels were significantly reduced in failing hearts. Additionally, phospholamban phosphorylation (serine-16 and threonine-17 sites) and myocardial cAMP content were both attenuated. The alterations in SR protein levels were also accompanied by a decreased V(max)and an increased EC50 (diminished apparent affinity) of SR Ca2+-uptake for Ca2+ in failing myocardia. Myocardial protein levels and Ca2+ uptake parameters were then analyzed with respect to gender, which revealed that the decreases in phosphorylated serine-16 were specific to male failing hearts, reflecting increases in the EC50 values of SR Ca2+-uptake for Ca2+, compared to donor males. These findings suggest that although decreased SERCA protein and phospholamban phosphorylation levels contribute to depressed SR Ca2+-uptake and left ventricular function in heart failure, the specific subcellular alterations which underlie these effects may not be uniform with respect to gender.
J Mol Cell Cardiol 2001 Jul
PMID:Gender influences on sarcoplasmic reticulum Ca2+-handling in failing human myocardium. 1143 40


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