Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.2.1.31 (beta-glucuronidase)
 7,680 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have shown that hyperosmotic media inhibit secretion in many cells and this has been interpreted to be a direct effect on membrane fusion during exocytosis. This conclusion is complicated, however, by our recent study in neutrophils (Biochim. Biophys. Acta 931: 175-179, 1987) showing that both calcium signals and enzyme release are inhibited by hyperosmolality. In this report, we extend these observations by demonstrating that chemotactic peptide formylmethionyl-leucyl-phenylalanine (FMLP)-induced enzyme release, secretory granule-plasma membrane fusion, and cytosolic calcium signals are all inhibited by similar increases in medium osmolality. The extent of beta-glucuronidase release is decreased in hyperosmotic media and its dose dependence is shifted to higher FMLP concentrations. Inhibition is rapid, reversible, and independent of osmoticant. Freeze-fracture replicas of quick-frozen neutrophils show that granules of cells stimulated in hyperosmotic media do not undergo fusion nor do they have specialized interactions with the plasma membrane or with membranes of adjacent granules. Calcium signals monitored and quantitated by indo-1 fluorescence during secretion confirmed the presence of three phases the calcium dependence of which we have described previously: 1) an initial peak of calcium that is independent of extracellular calcium and is inhibited 70% at high osmolality; 2) a broad shoulder of elevated calcium levels 30-90 s after stimulation that is dependent on extracellular calcium and is totally blocked at high osmolality; and 3) a plateau of lower but above basal calcium 2-5 min after stimulation that is dependent on extracellular calcium but is relatively unaffected by high osmolality. These results suggest that the FMLP-elicited calcium signal is a composite of multiple signaling events and that hyperosmotic inhibition of secretion, at least in neutrophils, may result from an impaired calcium signal in addition to the direct effect it has on exocytosis.
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PMID:Hyperosmotic inhibition of calcium signals and exocytosis in rabbit neutrophils. 336 56

Mucopolysaccharidosis VII, a classical lysosomal storage disease, is caused by deficiency of the enzyme beta-glucuronidase. Central nervous system (CNS) manifestations are severe with accumulations of storage vacuoles in all cell types. Intraventricular gene transfer can lead to transduction of the ependyma, with production and secretion of beta-glucuronidase into the cerebral spinal fluid and underlying cortex resulting in reversal of disease pathology restricted to the periventricular areas. We tested if systemic hyperosmolality would increase the distribution of beta-glucuronidase in brain parenchyma after intraventricular virus injection. Mice were administered mannitol, intraperitoneally, 20 days after gene transfer and 1 day prior to sacrifice. Mannitol-induced systemic hyperosmolality caused a marked penetration of beta-glucuronidase into the brain parenchyma. If mannitol was administered at the time of the intraventricular injection of virus, there was penetration of vector across the ependymal cell layer, with infection of cells in the subependymal region. This also resulted in increased beta-glucuronidase activity throughout the brain. Sections of brains from beta-glucuronidase-deficient mice showed correction of cellular pathology in the subependymal region plus cortical structures away from the ventricular wall. These data indicate that virus-mediated gene transfer to the brain via the ventricles, coupled with systemic mannitol administration, can lead to extensive CNS distribution of beta-glucuronidase with concomitant correction of the storage defect. Our findings have positive therapeutic implications for the treatment of CNS disorders with gene transfer vectors and recombinant proteins.
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PMID:Systemic hyperosmolality improves beta-glucuronidase distribution and pathology in murine MPS VII brain following intraventricular gene transfer. 1063 Jan 95