Glutamine synthetase (GS) activity in cultured rat astrocytes was measured in extracts and compared to the intracellular rate of glutamine synthesis by intact control astrocytes or astrocytes exposed to 1 mM 8-bromo-cAMP (8Br-cAMP) + 1 microM dexamethasone (DEX) for 4 days. GS activity in extracts of astrocytes treated with 8Br-cAMP + DEX was 7.5 times greater than the activity in extracts of control astrocytes. In contrast, the intracellular rate of glutamine synthesis by intact cells increased only 2-fold, suggesting that additional intracellular effectors regulate the expression of GS activity inside the intact cell. The rate of glutamine synthesis by astrocytes was 4.3 times greater in MEM than in HEPES buffered Hank's salts. Synthesis of glutamine by intact astrocytes cultured in MEM was independent of the external glutamine or ammonia concentrations but was increased by higher extracellular glutamate concentrations. In studies with intact astrocytes 80% of the original [U-14C]glutamate was recovered in the medium as radioactive glutamine, 2-3% as aspartate, and 7% as glutamate after 2 hours for both control and treated astrocytes. The results suggest: (1) astrocytes are highly efficient in the conversion of glutamate to glutamine; (2) induction of GS activity increases the rate of glutamate conversion to glutamine by astrocytes and the rate of glutamine release into the medium; (3) endogenous intracellular regulators of GS activity control the flux of glutamate through this enzymatic reaction; and (4) the composition of the medium alters the rate of glutamine synthesis from external glutamate.
Glucocorticoid hormones cause marked muscular atrophy, the mechanism of which is unknown. We employed a potent glucocorticoid antagonist, RU38486 [11 beta-(4-dimethylaminophenyl)17 beta-hydroxy-17 alpha-(prop-1-ynyl)estra-4,9-dien-3-one], to determine whether intracellular glucocorticoid receptors are involved. RU38486 was shown to be an effective blocker of glucocorticoid receptor binding in vivo and in vitro. Furthermore, this compound significantly blocked the loss of body and muscle weight caused by injection of dexamethasone. These data indicate that intracellular glucocorticoid receptors are important in the etiology of steroid myopathy. Studies with glucocorticoid antagonists may lead to the design of specific therapeutic modalities for the treatment of both endogenously and exogenously produced steroid myopathies.
A deletion of the long arm of chromosome 15 (usually involving bands 15q11-q12) has been seen in approximately 50% of Prader-Willi syndrome (PWS) patients [Ledbetter et al, 1982]. However, 14 patients with non-PWS (or atypical PWS) phenotype with 15q deletion indicate great clinical variability. A deletion was found in a propositus with a de novo translocation [45,XY, -15, -22, +rec(15;22) (22pter----22q13.2::15q14----15qter)], who had anomalies not normally observed in PWS patients. Activities of several enzymes mapped to the involved chromosomes were studied in the patient and control individuals. A 50% decrease in the level of arylsulfatase-A confirmed a small deletion in 22q(22q13.2----qter), and additional studies localized more precisely the loci for alpha-mannosidase (cytoplasmic) and beta-galactosidase.
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