Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although Ca(2+)/calmodulin-dependent protein kinase-II (CaMK) is known to phosphorylate different Ca(2+) cycling proteins in the cardiac sarcoplasmic reticulum (SR) and regulate its function, the status of CaMK in heart failure has not been investigated previously. In this study, we examined the hypothesis that changes in the CaMK-mediated phosphorylation of the SR Ca(2+) cycling proteins are associated with heart failure. For this purpose, heart failure in rats was induced by occluding the coronary artery for 8 weeks, and animals with >30% infarct of the left ventricle wall plus septum mass were used. Noninfarcted left ventricle was used for biochemical assessment; sham-operated animals served as control. A significant depression in SR Ca(2+) uptake and release activities was associated with a decrease in SR CaMK phosphorylation of the SR proteins, ryanodine receptor (RyR), Ca(2+) pump ATPase (SR/endoplasmic reticulum Ca(2+) ATPase [SERCA2a]), and phospholamban (PLB) in the failing heart. The SR protein contents for RyR, SERCA2a, and PLB were decreased in the failing hearts. Although the SR Ca(2+)/calmodulin-dependent CaMK activity, CaMK content, and CaMK autophosphorylation were depressed, the SR phosphatase activity was enhanced in the failing heart. On the other hand, the cAMP-dependent protein kinase-mediated phosphorylation of RyR and PLB was not affected in the failing heart. On the basis of these results, we conclude that alterations in SR CaMK-mediated phosphorylation may be partly responsible for impaired SR function in heart failure.
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PMID:Sarcoplasmic reticulum Ca(2+)/Calmodulin-dependent protein kinase is altered in heart failure. 1072 Apr 22

The excessive increase in intracellular Ca2+ concentration is associated with events linking cerebral blood flow reduction to neuronal cell damage. We have investigated the possible effect of ischemia and ischemia-reperfusion injury on endoplasmic reticulum (ER) Ca2+ transport. Two different models of ischemia as well as two different anesthetics were used. 5 min and 15 min of global forebrain ischemia caused significant depression of the rate of microsomal Ca2+ accumulation in pentobarbital anesthetised gerbils. The Ca2+ uptake activity recovered partially after 1 hour of reperfusion. Unlike pentobarbital anesthetised gerbils, no significant changes were detected in the active microsomal Ca(2+)-transport after 10 min of global forebrain ischemia in gerbil forebrain and hippocampus under halothane anesthesia. In addition, using the model of decapitation ischemia, we observed significant changes of the Ca2+ uptake in both halothane and pentobarbital anesthetised gerbils. These findings indicate that ischemic insult alters the brain microsomal Ca2+ transport which is not due to inhibition of the Ca(2+)-ATPase activity. However, the effect of ischemia on this transport system is dependent on the model of ischemia and on the type of anesthetics.
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PMID:Ischemia-induced inhibition of active calcium transport into gerbil brain microsomes: effect of anesthetics and models of ischemia. 1078 14

The effect of protein undernutrition on the activity of the smooth endoplasmic reticulum (microsomal) Ca2+-ATPase (SERCA) was investigated. After 12 weeks of ad libitum ingestion of low protein diet (5% protein), a significant depression (p <0.05) of liver ER Ca2+-ATPase activity (68.6% depression) was observed. However, no significant effects on cytochrome P450 activity and relative liver weight were found. It is proposed that low protein diet by inhibiting the rat liver SERCA activity, might increase the cytosolic free calcium ion concentration ([Ca2+]) and promote the development of liver tumor. The possible mechanisms of low protein diet induced inhibition of SERCA activity are highlighted.
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PMID:The Ca2+-transporting activity of rat liver microsomes in response to protein undernutrition: implications for liver tumor promotion. 1096 66

Rabbits were immunized with diphtheria toxoid combined with complete Freund's adjuvant. Half of the animals were started on intramuscular injections of chloramphenicol 24 hr before the injection of the antigens. There was a general depression of protein synthesis in the immune system in the presence of chloramphenicol, but a greater effect on the synthesis of antibody than on the synthesis of proteins necessary for reproduction and maturation. In contrast to the finding of antibody in cells of the spleen and in the circulation of the control animals, those animals receiving chloramphenicol did not have measurable circulating antibody, and their spleens contained only a few cells with intracytoplasmic antibody late in the course of the experiment. Cytologically there was maturation of potential antibody-producing cells in the red pulp and nonfollicular white pulp of the spleen while the animals were receiving chloramphenicol. These cells developed more slowly, and were fewer and smaller than those of the control animals. They had numerous small, electron-opaque particles in their cytoplasm early in development. Ribosomes were synthesized, though fewer in number. The endoplasmic reticulum formed more slowly.
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PMID:Differentiation and functional expression of potential antibody-producing cells in the presence of chloramphenicol. 1097 31

We have used rats and mice with mutations in myosin-Va to evaluate the range and function of IP3-mediated Ca2+ signaling in dendritic spines. In these mutants, the endoplasmic reticulum and its attendant IP3 receptors do not enter the postsynaptic spines of parallel fiber synapses on cerebellar Purkinje cells. Long-term synaptic depression (LTD) is absent at the parallel fiber synapses of the mutants, even though the structure and function of these synapses otherwise appear normal. This loss of LTD is associated with selective changes in IP3-mediated Ca2+ signaling in spines and can be rescued by photolysis of a caged Ca2+ compound. Our results reveal that IP3 must release Ca2+ locally in the dendritic spines to produce LTD and indicate that one function of dendritic spines is to target IP3-mediated Ca2+ release to the proper subcellular domain.
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PMID:Local calcium release in dendritic spines required for long-term synaptic depression. 1108 97

Darier disease (DD) is with a frequency of up to 1 in 36,000 a relatively common genodermatosis with autosomal dominant inheritance and late age of onset. The progressive skin manifestations are variable, but often debilitating and disfiguring, and may be associated with a wide range of neuropsychiatric problems, such as epilepsy and depression. On histology, acantholysis and dyskeratosis are prominent findings, implicating impaired functionality of desmosomes. Recently, mutations in the ATP2A2 gene encoding SERCA2, a calcium pump of the endo/sacrcoplasmic reticulum, have been identified as the molecular basis of DD. This slow-twitched calcium ATPase has two splice variants, one of which is highly expressed in epidermis, and maintains low intracellular calcium levels by facilitating transport of cytosolic calcium into the endoplasmic reticulum. Thus, it may confer a direct effect on the established calcium-dependent assembly of desmosomes. We screened ATP2A2 in a cohort of 24 DD families using conformation sensitive gel electrophoresis and direct sequencing, and detected 14 distinct mutations, 9 of which were novel. The mutational spectrum included 9 missense mutations, 1 nonsense mutation, 3 small in-frame deletions, and a 19-basepair insertion. Mutations were scattered over the entire gene with a slight preponderance in the first 8 exons, and affected exclusively residues conserved among all SERCAs. In addition, we found 2 silent polymorphisms, 1 of which occurred in 4 unrelated families. Comparison of molecular data and phenotypic features, such as severity and type of disease, occurrence of mucosal involvement, or association with neuropsychiatric disorders, did not reveal an obvious genotype-phenotype correlation in our cohort.
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PMID:Darier disease--novel mutations in ATP2A2 and genotype-phenotype correlation. 1116 76

Plasmalogens are glycerophospholipids of neural membranes containing vinyl ether bonds. Their synthetic pathway is located in peroxisomes and endoplasmic reticulum. The rate-limiting enzymes are in the peroxisomes and are induced by docosahexaenoic acid (DHA). Plasmalogens often contain arachidonic acid (AA) or DHA at the sn-2 position of the glycerol moiety. The receptor-mediated hydrolysis of plasmalogens by cytosolic plasmalogen-selective phospholipase A2 generates AA or DHA and lysoplasmalogens. AA is metabolized to eicosanoids. The mechanism of signaling with DHA is not known. The plasmalogen-selective phospholipase A2 differs from other intracellular phospholipases A2 in molecular mass, kinetic properties, substrate specificity, and response to glycosaminoglycans, gangliosides, and sialoglycoproteins. A major portion of [3H]DHA incorporated into neural membranes is found at the sn-2 position of ethanolamine glycerophospholipids. Studies with a mutant cell line defective in plasmalogen biosynthesis indicate that the incorporation of DHA is reduced in this RAW 264.7 cell line by 50%. In contrast, the incorporation of AA remains unaffected. This is reversed completely when the growth medium is supplemented with sn-1-hexadecylglycerol, suggesting that DHA can be selectively targeted for incorporation into plasmalogens. We suggest that deficiencies of DHA and plasmalogens in peroxisomal disorders, Alzheimer's disease (AD), depression, and attention deficit hyperactivity disorders (ADHD) may be responsible for abnormal signal transduction associated with learning disability, cognitive deficit, and visual dysfunction. These abnormalities in the signal-transduction process can be partially corrected by supplementation with a diet enriched with DHA.
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PMID:Plasmalogens, phospholipase A2, and docosahexaenoic acid turnover in brain tissue. 1147 81

Polychlorinated biphenyls (PCBs) are ubiquitous and persistent pollutants whose role in developmental toxicity is of great concern. The observation that the offspring of PCB-exposed mothers (both in humans and rodents) display reduced body mass prompted us to investigate the effects of commercial mixtures of PCB congeners (Aroclor 1232, 1254, and 1262) on differentiation of both a myogenic cell line and primary myogenic cell cultures. The fusion of L6 myoblasts into multinucleated myotubes and the increase of creatine kinase (CK) activity were dose-dependently inhibited by Aroclor 1254 at concentrations (0.1-4 microg/ml) that caused no effect on cell density. Ultrastructural analysis demonstrated that Aroclor 1254 also prevented the accumulation of contractile filaments while inducing hypertrophy of the smooth endoplasmic reticulum and appearance of membrane-filled autophagosomes. Half-maximal inhibition (IC50) of CK activity accumulation occurred at 0.01 microg/ml for Aroclor 1262, 2 microg/ml for Aroclor 1254, and 8 microg/ml for Aroclor 1232. Aroclor-dependent inhibition of myogenic differentiation was also shown by the reduced expression and nuclear accumulation of beta-galactosidase in primary cultures of fetal myoblasts from transgenic mice expressing this reporter gene under the control of the myosin light chain promoter. These data show that skeletal muscle differentiation is specifically impaired by PCBs and may explain the reported depression of body mass growth in PCB-exposed offspring at birth. Furthermore, myogenic cell cultures are highly sensitive to PCBs and allow the detection of biological effects of environmental levels of these pollutants.
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PMID:Polychlorobiphenyls inhibit skeletal muscle differentiation in culture. 1155 21

The Ras-like Rab GTPases regulate vesicle transport in endocytosis and exocytosis. We found that cardiac Rabs1, 4, and 6 are upregulated in a dilated cardiomyopathy model overexpressing beta(2)-adrenergic receptors. To determine if increased Rab GTPase expression can contribute to cardiomyopathy, we transgenically overexpressed in mouse hearts prototypical Rab1a, the small G protein that regulates vesicle transport from endoplasmic reticulum to and through Golgi. In multiple independent mouse lines, Rab1a overexpression caused cardiac hypertrophy that progressed in a time- and transgene dose-dependent manner to heart failure. Isolated cardiac myocytes were hypertrophied and exhibited contractile depression with impaired calcium reuptake. Ultrastructural analysis revealed enlarged Golgi stacks and increased transitional vesicles in ventricular myocytes, with increased secretory atrial natriuretic peptide granules and degenerative myelin figures in atrial myocytes; immunogold studies localized Rab1a to these abnormal vesicular structures. A survey of hypertrophy signaling molecules revealed increased protein kinase C (PKC) alpha and delta, and confocal microscopy showed abnormal subcellular distribution of PKCalpha in Rab1a transgenics. These results indicate that increased expression of Rab1 GTPase in myocardium distorts subcellular localization of proteins and is sufficient to cause cardiac hypertrophy and failure.
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PMID:Increased myocardial Rab GTPase expression: a consequence and cause of cardiomyopathy. 1173 71

Here we summarises the results of experimental investigation of changes in intracellular calcium homeostasis in sensory neurones of rats with streptozotocin-induced diabetes mellitus. Decrease in the calcium-accumulating function of both inositol-trisphosphate- as well as caffeine-sensitive endoplasmic reticulum has been detected both in primary sensory neurones of dorsal root ganglia and in secondary neurones of the spinal cord dorsal horn. Predominant depression in the functioning of metabotropic receptors of ligand-gated channels compared with those of ionotropic ones has been demonstrated. Changes in the pharmacological sensitivity of potential-operated calcium channels (predominantly of L-type), linked, probably, with alterations of functional connections between membrane channels and endoplasmic reticulum, are described. A predominant role of changes in the functioning of intracellular Ca(2+)-accumulating structures, leading to prolongation of depolarisation-induced Ca2+ transients in primary and secondary sensory neurones and corresponding changes in the transmission of nociceptive signals during diabetic neuropathy are discussed.
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PMID:[Changes in intracellular mechanisms in sensory neurons in experimental diabetes mellitus]. 1175 62


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