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Query: UNIPROT:P06889 (Mol)
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This study examined the alterations in sarcoplasmic reticulum (SR) Ca2+ sequestration function in homogenates during eccentric exercise and recovery and following additional eccentric exercise, and correlated these alterations with changes in force output. Eight healthy, untrained females, aged 20-25 years, cycled for a total of 60 min on an eccentric cycle ergometer (30 min at 66+/-3% VO2 peak and 30 min at 76+/-3% VO2 peak, determined during concentric exercise). Biopsies (extracted from the vastus lateralis) were taken before and after the exercise as well as on days 2, 6 and prior to and following identical exercise on day 14. Ca2+-uptake (nmol/min/mg protein) was unaffected (p > 0.05) following the first session of eccentric exercise; however, by day 2 a depression in uptake (p < 0.05) was observed which persisted throughout the remainder of the experiment. Maximal Ca2+-ATPase activity (nmol/min/mg protein) was elevated (p < 0.05) immediately following the first exercise session, remained elevated through day 2 and returned to pre-exercise levels by day 6 of recovery and increased again by day 14. No changes in either Ca2+-ATPase activity or Ca2+-uptake were observed with exercise on day 14. Both eccentric sessions, performed on days 0 and 14, resulted in similar depressions in force (p < 0.05) immediately following exercise. By day 2 force had recovered to pre-exercise levels. The results demonstrate that a prolonged alteration in SR Ca2+-uptake occurs following eccentric work that is unaccompanied by parallel changes in either SR Ca2+-ATPase activity or mechanical performance.
Mol Cell Biochem 1999 Dec
PMID:Alterations in sarcoplasmic reticulum function in female vastus lateralis with eccentric exercise. 1070 91

The purpose of this study was to evaluate the mechanism by which Escherichia coli lipopolysaccharide stimulates the secretion of phosphatidylcholine in primary cultures of rat type II pneumocytes. The stimulatory effect of lipopolysaccharide on phosphatidylcholine secretion was additive to those of terbutaline and TPA (protein kinase A and C activators respectively) and this effect was not suppressed by inhibitors of both protein kinases. On the other hand, lipopolysaccharide did not modify the increase on phosphatidylcholine secretion induced by the endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin, and enhanced slightly the calcium-ionophore A23187 stimulated phosphatidylcholine secretion. In addition, the stimulatory effect of lipopolysaccharide was suppressed by BAPTA, an intracellular Ca2+ chelator, and KN-62, a specific inhibitor of Ca2+-calmodulin-dependent protein kinase. These results, together with the lipopolysaccharide-mediated increase in the cytosolic [Ca2+], suggest that stimulation of phosphatidylcholine secretion by lipopolysaccharide in type II pneumocytes occurs by a calcium-dependent transduction mechanism via Ca2+-calmodulin-dependent protein kinase activation.
Mol Cell Biochem 2000 Feb
PMID:Involvement of calcium in the stimulation of phosphatidylcholine secretion in primary cultures of rat type II pneumocytes by Escherichia coli lipopolysaccharide. 1082 20

UTP activates P2Y, receptors in both 1321N1 cell transfectants expressing the P2Y2 receptor and human HT-29 epithelial cells expressing endogenous P2Y, receptors with an EC50 of 0.2-1.0 microM. Pretreatment of these cells with UTP diminished the effectiveness of a second dose of UTP (the IC50 for UTP-induced receptor desensitization was 0.3-1.0 microM for both systems). Desensitization and down-regulation of the P2Y2 nucleotide receptor may limit the effectiveness of UTP as a therapeutic agent. The present studies investigated the phenomenon of P2Y2 receptor desensitization in human 1321N1 astrocytoma cells expressing recombinant wild type and C-terminal truncation mutants of the P2Y2 receptor. In these cells, potent P2Y2 receptor desensitization was observed after a 5 min exposure to UTP. Full receptor responsiveness returned 5-10 min after removal of UTP. Thapsigargin, an inhibitor of Ca2+-ATPase in the endoplasmic reticulum, induced an increase in the intracellular free calcium concentration, [Ca2+]i, after addition of desensitizing concentrations of UTP, indicating that P2Y2 receptor desensitization is not due to depletion of calcium from intracellular stores. Single cell measurements of increases in [Ca2+]i induced by UTP in 1321N1 cell transfectants expressing the P2Y2 receptor indicate that time- and UTP concentration-dependent desensitization occurred uniformly across a cell population. Other results suggest that P2Y2 receptor phosphorylation/dephosphorylation regulate receptor desensitization/resensitization. A 5 min preincubation of 1321N1 cell transfectants with the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA), reduced the subsequent response to UTP by about 50%, whereas co-incubation of PMA with UTP caused a greater inhibition in the response. The protein phosphatases-1 and -2A inhibitor, okadaic acid, partially blocked resensitization of the receptor. Furthermore, C-terminal truncation mutants of the P2Y2 receptor that eliminated several potential phosphorylation sites including two for PKC were resistant to UTP-, but not phorbol ester-induced desensitization. Down regulation of protein kinase C isoforms prevented phorbol ester-induced desensitization but had no effect on agonist-induced desensitization of wild type or truncation mutant receptors. These results suggest that phosphorylation of the C-terminus of the P2Y2 receptor by protein kinases other than protein kinase C mediates agonist-induced receptor desensitization. A better understanding of the molecular mechanisms of P2Y2 nucleotide receptor desensitization may help optimize a promising cystic fibrosis pharmacotherapy based on the activation of anion secretion in airway epithelial cells by P2Y, receptor agonists.
Mol Cell Biochem 2000 Feb
PMID:Mechanisms of agonist-dependent and -independent desensitization of a recombinant P2Y2 nucleotide receptor. 1082 29

We previously reported that cytosolic calcium transiently increases after reversal of the sarcolemmal Na+/Ca2+-exchanger. Calcium released from sarcoplasmic reticulum (SR) constituted the major part of this cytosolic transient. The aim of this study was to test whether reversal of the Na+/Ca2+-exchanger affects SR calcium content, and whether altered SR calcium content is associated with direct triggering of SR calcium release or calcium release secondary to SR calcium overload. To this purpose we studied the change of SR calcium content after reversal of the Na+/Ca2+-exchanger and the dependence on the magnitude of change of its free energy (delta Gexch) in isolated rat ventricular myocytes. The Na+/Ca2+-exchanger was reversed by abrupt reduction of extracellular sodium ([Na+]o). The magnitude of change of deltaGexch was varied with [Na+]o. Cytosolic free calcium ([Ca2+]i) was measured with indo-1 and SR calcium content was estimated from the increase of [Ca2+]i after rapid cooling (RC). SR function was manipulated either by blockade of the SR Ca2+-ATPase with thapsigargin or by blockade of SR calcium release channels with tetracaine. Reversal of the Na+/Ca2+-exchanger caused a transient increase of [Ca2+]i of about 180 s duration with a time to peak of about 30 s. During the first 30 s rapid small amplitude cytosolic calcium fluctuations were superimposed on this transient. The magnitude of the response of [Ca2+]i to RC, during the course of the cytosolic [Ca2+]i transient, also transiently increased from 174 in control myocytes to 480 nmol/l at the time of the peak value. After correction of [Ca2+]i data for the fraction of mitochondrially compartmentalized indo-1 and mitochondrial calcium, total calcium released from SR after RC was calculated with the use of literature data on cytosolic calcium buffer capacity. Contrary to the measured RC-dependent increase of measured [Ca2+]i, after reversal of the Na+/Ca2+-exchanger, calculated total calcium released from SR transiently decreased. The extent of SR calcium depletion after reversal of the Na+/Ca2+-exchanger increased with the magnitude of change of deltaGexch. Restitution of [Na+]o 30 s after reversal of the Na+/Ca2+-exchanger, greatly accelerated both recovery of [Ca2+]i and SR calcium content. Pretreatment of myocytes with thapsigargin caused almost entire depletion of SR and substantial reduction of the cytosolic transient of [Ca2+]i following reversal of the Na+/Ca2+-exchanger. Application of tetracaine hardly affected SR calcium content, but caused an increase of the SR calcium content following reversal of the Na+/Ca2+-exchanger, while the cytosolic transient increase of [Ca2+]i was substantially reduced. We conclude that reversal of the Na+/Ca2+-exchanger directly triggers SR calcium release and decreases SR calcium content in a deltaGexch dependent manner.
J Mol Cell Cardiol 2000 Jun
PMID:SR calcium depletion following reversal of the Na+/Ca2+-exchanger in rat ventricular myocytes. 1088 55

The plasma membrane Ca2+-ATPase is a well known enzyme in eucaryotes able to extrude calcium to the extracellular space in order to restore intracellular calcium to very low levels. This ATPase needs plasma membrane lipids such as acidic phospholipids in order to maintain its activity. In this study, we investigated the role that calcium and cholesterol play on the thermal stability of the Ca2+-ATPase isolated from cardiac sarcolemma and erythrocyte membranes. Calcium showed a stabilizing and protective effect when the enzyme was exposed to high temperatures. This stabilizing effect showed by calcium was potentiated in the presence of cholesterol. These protection effects were reflected on several thermodynamic parameters such as T50, deltaHvh and apparent deltaG, indicating that calcium might induce a conformational change stabilized in the presence of cholesterol that confers enzyme thermostability. The effect shown by cholesterol on deltaHvh and apparent deltaH++ open the possibility that this lipid decreases cooperativity during the induced transition. Despite that a binding site for cholesterol has not been identified in the plasma membrane Ca2+-ATPase, our results supports the proposal that this lipid interacts with the enzyme in a direct fashion.
Mol Cell Biochem 2000 Jun
PMID:Thermal analysis of the plasma membrane Ca2+-ATPase. 1094 7

Domoic acid is a shellfish toxin which produces neurodegeneration and CNS dysfunction, notably a loss of short-term memory. This toxin was found in blue mussels (Mytilus edulis) cultivated in river water in the east coast of Prince Edward Island in Canada and caused human poisoning. The toxin was localized in the stomach of blue mussels, which was engorged with algae, Nitzschia pungens, that were filtered from the surrounding water. The toxin was isolated from contaminated mussels or phytoplankton, and identified chemically as domoic acid (DOM) which is a tricarboxylic amino acid. Due to its structural resemblance to glutamic, aspartic and kainic acids, DOM was considered to produce excitotoxicity by similar mechanism(s). However, the latest evidence indicates differences in its mode of action from these excitatory agonists. We propose that DOM induces toxicity via changes in intracellular concentration of Ca2+ ([Ca2+]i). Results of our studies demonstrate that DOM elevated [Ca2+]i in brain slices. Glucose deprivation and removal of Na+ from the Krebs-bicarbonate medium further elevated [Ca2+]i, suggesting a relationship between glucose metabolism (cell energy), Na+ and Ca2+ transfer across neuronal membrane. DOM-induced rise in [Ca2+]i was due to enhanced Ca2+ influx and its mobilization from the endoplasmic reticulum. In addition, diminished Ca2+-ATPase activity due to lack of ATP, and variable amounts and expression of calcium binding proteins (CaBP) appear to contribute to an elevation in [Ca2+]i in response to DOM. Most interestingly, DOM inhibited Ca2+ and calmodulin-stimulated adenylate cyclase activity in brain membranes, resulting in reduced level of cyclic AMP. Cyclic AMP is known to activate protein kinase A to enhance phosphorylation of Ca2+ channels, thereby, reducing Ca2+ influx to prevent the development of Ca2+ overload which is detrimental to neuronal cell function (neuroprotection). However, DOM reduced cyclic AMP level, diminishing the feedback control of cyclic AMP on Ca2+ influx via Ca2+ channels, thereby, allowing continuing enhanced Ca2+ influx, resulting in Ca2+ overload which adversely affects many intracellular processes to induce toxicity. Ca2+ and CaM-stimulated adenylate cyclase activity in brain is highly correlated with the acquisition and retention of memory in different organisms. Calcium binding proteins bind Ca2+ reversibly and provide intracellular Ca2+ buffering, thereby, protecting neuronal cell from damage by Ca2+ overload in response to DOM. DOM appears to interfere with the cross talk between Ca2+ and cyclic AMP which is necessary for neuronal cell function. We have also demonstrated that DOM stimulates GLU release from synaptosomes and may produce some of its toxic effects via excess GLU in the neuronal synapse. In conclusion, DOM-induced neurodegeneration resulting in a loss of memory is mediated by Ca2+ overload, inhibition of Ca2+ and CaM-stimulated adenylate cyclase activity, and/or by the enhanced GLU release in rat brain.
Int J Mol Med 2000 Oct
PMID:Domoic acid-induced neurodegeneration resulting in memory loss is mediated by Ca2+ overload and inhibition of Ca2+ + calmodulin-stimulated adenylate cyclase in rat brain (review). 1099 28

We screened for mutant strains of Saccharomyces cerevisiae that are sensitive to overexpression of specific cyclins, and identified mutations in two genes that caused growth inhibition in response to mild overexpression of Clb3. One was the ANP1 gene, which encodes a glycosyltransferase previously identified by a similar strategy using Clb2 instead of Clb3. This paper describes the second strain of S. cerevisiae that is hypersensitive to Clb3 expression. The gene mutated in this strain was identified as PMR1, which encodes a Ca2+-ATPase located in the Golgi membrane. The protein product of pmr1-1 was truncated at residue 409 and thus lacked the C-terminal ATPase domain. The pmr1-1 strain was hypersensitive to over-expression of Clb3, but not Cln2, Clb5 or Clb2. The lethality due to Clb3 expression in pmr1-1 could be suppressed by adding Ca2+ ions to the medium. The pmr1-1 strain proved to be defective in glycosylation, and the defects in glycosylation were exacerbated by high levels of Clb3. On induction of Clb3 expression in the pmr1-1 strain, the cells arrested at anaphase with an elongated daughter bud. We discuss possible interpretations of this synthetic lethal phenotype.
Mol Gen Genet 2000 Sep
PMID:Isolation and characterisation of a mutation in the PMR1 gene encoding a Golgi membrane ATPase, which causes hypersensitivity to over-expression of Clb3 in Saccharomyces cerevisiae. 1101 30

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

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

Calcium level in organelles of the slime mold Physarum polycephalum was monitored by chlortetracycline, a low-affinity calcium indicator. It was found that 2,5'-di(tertbutyl)-1,4,-benzohydroquinone (BHQ) at a concentration of 100 microM, but not the highly specific inhibitor of sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), thapsigargin (1-10 microM), elicited calcium release from the CTC-stained intracellular calcium pool. Ionomycin also caused a calcium release (23.7+/-5.1%), which was less than that induced by BHQ (30.1+/-6.0%). Procaine (10 mM), a blocker of ryanodine receptor, completely abolished the responses to BHQ and ionomycin. Another blocker, ryanodine (100 microM), only slightly diminished the responses to ionomycin and BHQ. Apparently, BHQ and ionomycin acting as a Ca2+-ATPase inhibitor and an ionophore, respectively, elicit an increase in [Ca2+]i, which in turn triggers a calcium-induced calcium release (CICR) via the ryanodine receptor. Caffeine, an activator of ryanodine receptor, at a concentration of 25-50 mM produced a Ca2+-release (5.6-16.0%), which was not similar in magnitude to CICR. The response to 25 mM caffeine was only moderately inhibited by 25 mM procaine, and almost completely abolished by 50 mM procaine and 100 microM ryanodine.
Comp Biochem Physiol A Mol Integr Physiol 2001 Feb
PMID:Ionomycin and 2,5'-di(tertbutyl)-1,4,-benzohydroquinone elicit Ca2+-induced Ca2+ release from intracellular pools in Physarum polycephalum. 1122 89


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