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PubMed1997

The myxoma virus M-T4 gene encodes a novel RDEL-containing protein that is retained within the endoplasmic reticulum and is important for the productive infection of lymphocytes.

To investigate the contribution of the myxoma virus M-T4 gene to viral virulence, both copies of the M-T4 gene were inactivated by disruption and insertion of the Escherichia coli guanosine phosphoribosyltransferase gene. Infection of European rabbits with the recombinant M-T4-deleted virus, vMyxlacT4, resulted in disease attenuation. In contrast, infection of rabbits with vMyxlac elicited the classical features of lethal myxomatosis. A notable decrease in the number of secondary lesions in animals infected with vMyxlacT4 suggested an inability of the virus to disseminate in vivo. Infection of either a rabbit CD4+ T cell line, RL-5, or primary rabbit peripheral blood lymphocytes with vMyxlacT4- resulted in the rapid induction of apoptosis. Sequence analysis of M-T4 revealed both an N-terminal signal sequence and a C-terminal -RDEL sequence, suggesting that M-T4 resides in the endoplasmic reticulum. The M-T4 protein was found to be sensitive to endo H digestion and confocal fluorescence microscopy demonstrated that M-T4 colocalized with calreticulin, indicating that M-T4 is retained within the endoplasmic reticulum. Our results indicate that M-T4 is the first example of an intracellular virulence factor in myxoma virus that functions from within the endoplasmic reticulum and is necessary for the productive infection of lymphocytes.

Amino Acid Sequence↗
PubMed1980

Function of the sarcoplasmic reticulum (SR) in hypophosphatemic myopathy.

Lipid composition and Ca2+ transport properties were examined in the isolated sarcoplasmic reticulum of non-exercised muscles of markedly phosphorus depleted rats. Phosphorous depletion with a fall of plasma Pi from 8.04 +/- 0.85 to 2.56 +/- 0.48 mg/dl was accompanied by a decrease in muscle Pi and ATP content and by a significant decrease in the phospholipid/protein ratio of sarcoplasmic reticulum. The phosphatidyl -choline/phosphatidyl-ethanolamine ration in sarcoplasmic membranes was increased. Storing capacity for Ca2+ was significantly diminished. In contrast, there was no significant change of kinetic parameters of Ca2+ transport, i.e. of the initial rate of uptake and concentrating ability. These findings do not necessarily exclude changes of cytosolic Ca2+ concentration in phosphate depletion, but they exclude alterations of intrinsic kinetic properties of the sarcoplasmic reticulum as a cause of any such potential changes.

Animals↗
PubMed1983

Mediation of sarcoplasmic reticulum disruption in the ischemic myocardium: proposed mechanism by the interaction of hydrogen ions and oxygen free radicals.

Acute myocardial ischemia results in a decrease in developed tension and an increase in resting tension. A breakdown of the excitation-contraction coupling system can explain the behavior of the ischemic muscle at a subcellular level. We have identified a specific defect in the sarcoplasmic reticulum (SR) from the ischemic myocardium; i.e., the uncoupling of calcium transport from ATP hydrolysis. The mediators of this excitation-contraction uncoupling process have not been identified. It is now established that the intracellular pH of the ischemic myocardium is in the range of 6.4 but the role of protons and potential role of free radicals have not been identified. We have hypothesized that protons and free radicals may interact to produce the excitation-contraction uncoupling of the ischemic myocardium. Cardiac SR was isolated from the wall of canine left ventricle and calcium uptake velocity and Ca2+ stimulated-Mg2+ dependent ATPase activity determined. Increasing proton concentration between pH 7.0 and 6.4 significantly reduced calcium uptake rates (pH 7.0 = 0.95 +/- 0.02; 6.4 = 0.50 +/- 0.02 mumoles Ca2+/mg-min; p less than 0.01) with no effect on ATPase activity. Calculated coupling ratios (mumoles Ca2+/mumoles Pi) decreased from 0.87 +/- 0.06 at pH 7.0 to 0.51 +/- 0.05 at pH 6.4. At pH 7.0, the generation of exogenous free radicals from the xanthine-xanthine oxidase system significantly depressed both calcium uptake rates (Control = 0.95 +/- 0.02; X+XO = 0.15 +/- 0.02) and ATPase activity (Control = 1.05 +/- 0.02; X+XO + 0.30 +/- 0.01 mumoles Pi/mg-min; p less than 0.01). The decreases in calcium uptake and in ATPase activity were completely reversible with superoxide dismutase (SOD). At pH 6.4 in the presence of xanthine and xanthine oxidase, there is a further depression of calcium uptake rates (Control = 0.50 +/- 0.02; X+XO = 0.11 +/- 0.01; p less than 0.05) but there is no SOD reversible component. The addition of SOD + 20mM mannitol normalized calcium transport at pH 6.4. The calculated coupling ratio at pH 6.4 in the presence of free radicals was 0.13. In contrast sarcoplasmic reticulum isolated from ischemic myocardium demonstrated a significant depression of calcium uptake rates at pH 7.1 which was further accentuated at pH 6.4. Ca2+-ATPase was significantly depressed at pH 7.1 but there was no accentuation at pH 6.4. It is concluded that no single species of free radical can explain the intracellular excitation-contraction uncoupling of the ischemic myocardium. The system can be explained by the interaction of hydrogen ions and superoxide anions producing both injury to the sarcoplasmic reticulum and the formation of lipid free radicals with hydroxyl-like activity.

Adenosine Triphosphatases↗
PubMed1982

Effects of palmitic acid and palmityl carnitine on calcium sequestration by rabbit skeletal sarcoplasmic reticulum vesicles.

A number of long-chain fatty acids and fatty acid derivatives accumulate in the cytosol of ischemic myocardium. Although the functional significance of this accumulation in vivo remains unclear, these amphiphilic compounds may alter the functional properties of a variety of biological membranes in vitro. In this study, we investigated the effect of palmitic acid and palmityl carnitine on calcium sequestration by sarcoplasmic reticulum vesicles in the absence of calcium-precipitating anions. Palmitic acid, at micromolar concentrations, enhanced calcium sequestration in a concentration-dependent manner when present from the onset of the reaction or when added to calcium-filled vesicles. Under identical conditions, similar concentrations of palmityl carnitine inhibited calcium sequestration when present at the onset of the reaction and caused a rapid release of accumulated calcium when added to calcium-filled vesicles. Low concentrations of palmitic acid decreased the sensitivity of the sarcoplasmic reticulum to the inhibitory effects of palmityl carnitine. These results suggest that calcium pump function in the sarcoplasmic reticulum can be altered by the presence of amphiphilic compounds and that this alteration is dependent on both the structure and number of amphiphiles present.

Animals↗
PubMed1992

Immune-mediated modulation of sarcoplasmic reticulum function in human dilated cardiomyopathy.

Calcium transport by the cardiac sarcoplasmic reticulum is depressed in human dilated cardiomyopathy, but the mechanisms involved are not clear. The possible involvement of immunological mechanisms was explored by evaluating the effect of sera from 49 patients with dilated cardiomyopathy on oxalate-facilitated Ca2+ uptake. In 14 of these patients, serum or IgG induced a time- and concentration-dependent decline (29 +/- 4% at 100-fold serum dilution) in Ca2+ transport. In 14 patients, autoantibodies against the beta 1-adrenoceptor were also demonstrated by a ligand binding inhibition assay. Serum from these patients inhibited the isoproterenol-mediated stimulation of Ca2+ uptake in permeabilized cardiac myocytes, but did not prevent the effect of protein kinase A. Anti-beta-receptor antibodies were present in 50% of the sera inhibiting Ca2+ uptake compared to 20% of those without inhibitory activity, (p less than 0.01). There was a strong correlation between the inhibition of sarcoplasmic reticulum Ca2+ transport and the HLA-DR4 phenotype (78% compared to 30% in patients with no inhibitory effect). These results suggest that immunological mechanisms play an important role in modifying sarcoplasmic reticulum function in about a third of the patients with detailed cardiomyopathy.

Adult↗
PubMed1992

Calcium uptake by sarcoplasmic reticulum and its modulation by cAMP-dependent phosphorylation in normal and failing human myocardium.

ATP-dependent, oxalate-supported Ca2+ uptake by cardiac sarcoplasmic reticulum was examined in microsomes prepared from left-ventricular free wall myocardium obtained from the explanted failing hearts of transplant recipients with idiopathic dilated cardiomyopathy and the non-failing hearts of kidney donors for whose hearts no suitable recipients were available. There were no significant differences between the two groups with respect to values for Vmax, K0.5 (for Ca2+) or nHill of basal Ca2+ uptake. The stimulation of Ca2+ uptake associated with cAMP-dependent phosphorylation of phospholamban could be reproduced by incubation of microsomes with a monoclonal antibody to phospholamban. Stimulation resulted from a decrease in K0.5, with no changes in Vmax or nHill. The magnitude of stimulation of Ca2+ uptake following incubation with anti-phospholamban monoclonal antibody was identical in preparations from normal and failing hearts. Finally, sarcoplasmic reticulum-associated cGMP-inhibited cAMP phosphodiesterase activity in these preparations was characterised. Measurement of steady-state kinetics and pharmacologic sensitivity indicated that this activity was functionally homogeneous. Preparations from failing and non-failing hearts did not differ with respect to either values for Vmax and Km or susceptibility to inhibition by the cilostamide derivative OPC 3911. These observations indicate that abnormalities in the regulation of intracellular [Ca2+] in failing human myocardium cannot be ascribed to changes in the level or function of the Ca(2+)-transporting ATPase, phospholamban or cGMP-inhibited cAMP phosphodiesterase in the sarcoplasmic reticulum.

Antibodies, Monoclonal↗
PubMed1983

The existence of tubulo-cisternal endoplasmic reticulum in rat hepatocytes.

Rat livers were fixed by perfusion with glutaraldehyde via the portal vein and postfixed with a mixture of osmium tetroxide and potassium ferricyanide. Subsurface cisterns and vesicles were demonstrated, and, from serial sections, it appears that these organelles are part of large, fenestrated cisterns situated parallel to and at a distance of 20-40 nm from the lateral plasma membrane. Some of the cisterns possessed ribosomes on the surface facing the interior of the cell and, at points, they were continuous with the endoplasmic reticulum. From the lateral cisterns, tubules approached the plasma membrane facing the space of Disse and the sinusoid. A network of tubules was found in the vicinity of the bile canaliculus; a part of it lay close to the canalicular plasma membrane. Serial sectioning revealed that this network was continuous with the lateral cisterns via the endoplasmic reticulum. This morphology resembles that of tubulo-cisternal endoplasmic reticulum of such transporting epithelia as the choroid plexus and the renal proximal tubules.

Animals↗
PubMed1983

Sarcoplasmic reticulum and intermediate filament organization in cultured neonatal cardiac muscle cells. Studies with reduced osmium ferrocyanide.

Cardiac muscle cells from 3-day-old rat neonates were cultured for periods of 2 to 56 days. In order to facilitate ultrastructural studies on the organization of the sarcoplasmic reticulum, the cells were prepared for transmission electron microscopy according to a regimen including postfixation in reduced osmium ferrocyanide. The nonjunctional sarcoplasmic reticulum (NJSR) was organized as a loose, fenestrated sleeve around the exterior of bundles of myofilaments and was particularly prominent at the level of the Z line. The only recognizable junctional elements of the sarcoplasmic reticulum were in a peripheral location. Reduced osmium ferrocyanide was also useful in distinguishing intermediate (10 nm) filaments, since it understained Z substance, which often obscured these structures. Intermediate filaments were arranged both at the Z line and the intercalated disc, in parallel strands, approximately at right angles to the myofilaments.

Animals↗
PubMed1986

Shape and disposition of clefts, tubules, and sarcoplasmic reticulum in long and short sarcomere fibers of crab and crayfish.

The disposition of surface invaginations (clefts, Z and T tubules) and of the sarcoplasmic reticulum has been examined by electron microscopy at three accelerating voltages (100, 200 and 1000 kV) and by phase-contrast light microscopy in crustacean muscles infiltrated by the "Golgi stain." In long-sarcomere, tonic type fibers, an extensive system of invaginating clefts has been observed, along with both Z and T tubules. Z and T tubules form interconnections with each other, but only T tubules form specific contacts with the sarcoplasmic reticulum, which in these fibers forms an extended and continuously fenestrated network. In short-sarcomere, phasic type fibers, a ladder-like disposition of an abundant T network is found. Z tubules are absent in these fibers. The sarcoplasmic reticulum forms more frequent junctions with flattened areas of T tubules and with clefts, but has less extensive free surfaces than in the long-sarcomere fibers.

Animals↗
PubMed1986

Compartmentation of the rough endoplasmic reticulum.

It has become evident during recent years that a wide variety of proteins are synthesized on membrane-bound polysomes, very many of which are not ultimately secreted from the cell. The majority of proteins appear to go through some form of post-translational modification before the final appearance of an 'active' product, and in some cases the polypeptide chain may be modified before the completed protein molecule is released from the ribosome. This then raises the question concerning the possibility of the organization of the rough endoplasmic reticulum into individual domains, or compartments, each of which may have the responsibility of performing definite and well defined functions. During recent years the behaviour of two subfractions of the rough endoplasmic reticulum in a variety of cell types and under a variety of conditions has been studied in order to gain insight into a possible compartmentation of this organelle. Throughout the studies disruption of cells has been performed by nitrogen cavitation. This technique was chosen in order to provide conditions of homogenization which were extremely reproducible since shearing forces, mechanical damage and the effects of local heating were eliminated. Endoplasmic reticulum (ER) membranes isolated from the post-mitochondrial supernatant have been separated into subfractions by centrifugation on discontinuous sucrose gradients. By virtue of their high density imparted by the association of ribosomes, rough ER (RER) membranes penetrate 1.4 M sucrose accumulating above either 2.0 M sucrose (light rough -LR membranes) or a cushion of 2.3 M sucrose (heavy rough -HR membranes). Smooth (S) membranes, which are virtually devoid of ribosomes, collect above 1.4 M sucrose. The HR, LR and S subfractions in MPC-11 cells differ in a number of respects: RNA/protein and RNA/phospholipid ratios, polysome profiles and marker enzymes. When cells were homogenized in buffer containing 25 mM KCl then all three ER subfractions were observed, however, when the buffer contained 100 mM KCl then only the LR and S subfractions were observed in gradients, radioactivity equivalent to that in the HR fraction was not recovered in the other two subfractions. Four times as many light chain immunoglobulin polypeptides were found associated with polysomes of HR membranes compared to LR membranes. The nuclear associated ER (NER), though very active in protein synthesis, was only 20% as active in the synthesis of light chain as the combined LR/HR fraction. Studies with MPC-11 cells showed that the relative amounts of the three ER subfractions were related to the phase of the cell cycle.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1975

Ultrastructural evidence for a direct connection between the myocardial granules and the sarcoplasmic reticulum in the cardiac ventricle of Myxine glutinosa (L.).

The occurrence of structural connections between myocardial granules and tubular elements of the sarcoplasmic reticulum in the cardiac ventricle of the Atlantic hagfish is described. The core substance of the myocardial granules is shown to be uranophilic and in this respect similar to the granular cores within the lumen of the sarcoplasmic reticulum. After application of CaCl2-containing fixatives, the ultrastructure of the core substance of these organelles resembles that described for calcium-containing structures in vertebrate glial cells. Incidences of uranophilic core substance in the extracellular space suggest a secretory function of the myocardial granules. Possible implications of the sarcoplasmic reticulum and the myocardial granules in storage, intracellular transport, and secretion of bound calcium are discussed.

Animals↗
PubMed1983

Monovalent ion and calcium ion fluxes in sarcoplasmic reticulum.

The ion permeability of sarcoplasmic reticulum vesicles from skeletal and heart muscle has been characterized by radioisotope flux, osmotic and membrane potential measurements, and by incorporating vesicles into planar phospholipid bilayers. The sarcoplasmic reticulum membrane is uniquely permeable to various biologically relevant monovalent ions. At least two and possibly three separate passive permeation systems for monovalent ions have been identified: 1) a K+, Na+ channel, 2) an anion channel, and 3) a H+ (OH-) permeable pathway which may or may not be synonymous with the anion channel. A possible physiological function of these monovalent ion permeation systems is to permit rapid movement of K+, Na+, H+ and Cl- across the membrane counter electrogenic Ca2+ fluxes during Ca2+ release and uptake by sarcoplasmic reticulum.

Animals↗
PubMed1993

Activation and inhibition of the sarcoplasmic reticulum Ca2+ channel by the polycationic dyes Hoechst 33342 and Hoechst 33258.

The polycationic dyes, Hoechst 33342 (Bisbenzimide,2'-(4-ethoxyphenyl)-5-(4-methyl-1-piperazinyl)-2,5'-bi-1H- benzimidazole) and Hoechst 33258 (Bisbenzimide,2'-(4-hydroxyphenyl)-5-(4-methyl-1-piperazinyl)- 2,5'-bi-1H-benzimidazole) alter the activity of the sarcoplasmic reticulum Ca2+ channel. Although they act competitively, Hoechst 33342 decreases, while Hoechst 33258 increases, the rate of channel-mediated Ca2+ efflux from junctional sarcoplasmic reticulum vesicles. Unlike other cationic sarcoplasmic reticulum Ca2+ channel antagonists, Hoechst 33342 blocks the ryanodine-activated Ca2+ channel. Both Hoechst 33342 and Hoechst 33258 inhibit the channel incorporated into the planar lipid bilayer. Since the only structural difference between the two dyes is that the agonist Hoechst 33258 has a hydroxy group where the antagonist Hoechst 33342 has an ethoxy group, it is possible that the more hydrophobic, bulky ethoxy group blocks Ca2+ movement through the channel, whereas the hydroxy group only reduces the rate of Ca2+ movement.

Adenosine Triphosphate↗
PubMed1980

Ultrastructure of the human enamel organ. I. External enamel epithelium, stellate reticulum, and stratum intermedium.

The fine structure of external enamel epithelium, stellate reticulum and stratum intermedium in primary tooth germs (bell stage) from four human foetuses was investigated. Characteristically, the cells of the differentiated external enamel epithelium, stellate reticulum and stratum intermedium exhibit many free ribosomes, few rough endoplasmic reticulum cisterns, well-developed Golgi complexes, many coated and smooth vesicles, often in relation to the cell membranes, and many bundles of tonofilaments. The cells are connected by numerous desmosomes and gap junctions. A parallel differentiation of stratum intermedium - external enamel epithelium, and the ameloblast layer is demonstrated. The morphology of the cells of the three layers indicates that these have secretory, transport and supporting functions.

Cell Membrane↗
PubMedDate not supplied

Allosteric regulation of cardiac sarcoplasmic reticulum Ca-ATPase: a comparative study.

The mechanisms of allosteric regulation of the Ca-ATPases of cardiac and skeletal sarcoplasmic reticulum by ATP have been compared. Although both enzymes showed stimulation of ATPase activity by ATP, the cardiac enzyme did not show the plateau in ATPase activity at 10-100 microM ATP seen with the skeletal enzyme. Likewise the phosphoenzyme (EP) levels did not plateau with the cardiac enzyme as they did with the skeletal enzyme. The apparent negative cooperatively which was seen in the kinetics of ATP hydrolysis at low ATP concentrations was not due to negative cooperatively in substrate binding to either enzyme. The cardiac enzyme did show, however, much higher affinity for the ATP analog, AMPPCP, which helps explain how AMPPCP blocks ATPase activity in the cardiac enzyme and stimulates ATPase activity in the skeletal enzyme. Fluorescein isothiocyanate was used to determine if allosteric regulation takes place through site-site interactions in oligomers. The 1 to 1 ratio between AMPPCP binding sites and FITC binding sites eliminated allosteric regulation by effector sites in both enzymes. The allosteric mechanism which remained was one in which the active-site becomes an effector-site by the early departure of ADP in the reaction mechanism. The step stimulated by the binding of ATP at the active-site turned effector-site was a nonphosphorylated form of the enzyme in cardiac sarcoplasmic reticulum and a phosphorylated form in skeletal sarcoplasmic reticulum.

Adenosine Triphosphate↗
PubMed1986

Specialized contacts between sarcolemma and sarcoplasmic reticulum at the ends of muscle fibers in the diaphragm of the rat.

An electron-microscopic study of the myotendinous portion of the diaphragm in the Wistar rat has shown that at the ends of muscle fibers, longitudinally oriented invaginations and peripheral furrows of the sarcolemma establish specialized contacts with individual sacs of the sarcoplasmic reticulum. The construction of these terminal contacts is similar to that of contacts between sarcolemmic T-tubules and terminal cisternae of the sarcoplasmic reticulum, characterized by formation of triads. The contact zones of the sac membrane are undulated and bound to the adjoining sarcolemma via electron-dense profiles of varying forms. Frequently, the terminal contacts and triads are located at the same level within the muscle fiber, at the borderline between A- and I-bands of the sarcomeres. At the ends of muscle fibers combined contacts between peripheral furrows of the sarcolemma, terminal cisternae of the sarcoplasmic reticulum, and T-tubules of the triads are also disclosed. The implications of the terminal contacts for muscle contraction are discussed.

Animals↗
PubMed1989

AlF-4 inhibits the accumulation of Ca in the endoplasmic reticulum in intact myometrial strips, but not in the rabbit ear artery.

AlF-4, known to be a potent modulator of G-proteins, also inhibits purified "P"-type cation-transport ATPases (Missiaen et al. 1988). The aim of the present work is to find out whether AlF-4 also inhibits these ATPases in intact cells. We therefore have studied the effect of AlF-4 on the force development and on 45Ca2+ -fluxes of muscle strips from rat myometrium and rabbit ear artery. 1 mM-NaF plus 10 microM-AlCl3 induces in both tissues a tonic contraction that is completely blocked by 0.5 mM-deferoxamine. The contractile response in myometrium exceeds that of the ear artery. These contractions are independent of an activation of G-proteins but their amplitude depends on [Ca2+]o. Application of AlF-4 during the loading of the endoplasmic reticulum of myometrium with Ca2+ dramatically reduces the amount of stored Ca2+ as estimated from its release induced by 1 mM-carbachol during incubation in Ca-free solution. This effect could be due to a predominant inhibitory effect of AlF-4 on the (Ca2+ + Mg2+)-ATPase of the endoplasmic reticulum. Such effect could not be established in rabbit ear artery. The increase of the fractional loss of 45Ca2+ induced by 10 microM-norepinephrine in rabbit ear artery is not inhibited by AlF-4. It is concluded that the inhibition of the endoplasmic-reticulum (Ca2+ + Mg2+)-ATPase in intact myometrial cells warns us against explaining all effects of AlF-4 on intact cells only by an activation of G-proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Aluminum↗
PubMed1975

[Structure and function of the endoplasmic reticulum].

After a general review of enzyme topology and the molecular architecture of endoplasmic reticulum the latest research results are discussed. Microsomal enzymes do not occur in specialized regions of the endoplasmic reticulum but are uniformly distributed over the entire membrane system. Functionally associated enzymes are also located in the direct vicinity of the membrane. It has been shown that the catalytic activity of integral enzyme proteins depends on phospholipid and membrane structure. These membrane-bound lipoproteid complexes exert specific effects as vectorial enzyme catalysts. The endoplasmic reticulum is active is active in the intracellular transport of metabolites.

Animals↗