Beryllium competitively inhibits brain myo-inositol monophosphatase, but unlike lithium does not enhance agonist-induced inositol phosphate accumulation
| Autor: | Alice V. Bakker, Jackson Elisa Rose, W S Faraci, K Pratt, Stevin H. Zorn |
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| Rok vydání: | 1993 |
| Předmět: |
Lithium (medication)
Inositol Phosphates Lithium Binding Competitive Biochemistry Neuroblastoma chemistry.chemical_compound Tumor Cells Cultured medicine Animals Humans Inositol Phosphatidylinositol Inositol phosphate Molecular Biology IC50 chemistry.chemical_classification biology Hydrolysis Brain Cell Biology Phosphoric Monoester Hydrolases Rats Kinetics chemistry Mechanism of action Enzyme inhibitor biology.protein Cattle Beryllium medicine.symptom Uncompetitive inhibitor Research Article medicine.drug |
| Zdroj: | Biochemical Journal. 291:369-374 |
| ISSN: | 1470-8728 0264-6021 |
| Popis: | Despite limiting side-effects, lithium is the drug of choice for the treatment of bipolar depression. Its action may be due, in part, to its ability to dampen phosphatidylinositol turnover by inhibiting myo-inositol monophosphatase. Beryllium has been identified as a potent inhibitor of partially purified myo-inositol monophosphatase isolated from rat brain (Ki = 150 nM), bovine brain (Ki = 35 nM), and from the human neuroblastoma cell line SK-N-SH (Ki = 85 nM). It is over three orders of magnitude more potent than LiCl (Ki = 0.5-1.2 mM). Kinetic analysis reveals that beryllium is a competitive inhibitor of myo-inositol monophosphatase, in contrast with lithium which is an uncompetitive inhibitor. Inhibition of exogenous [3H]inositol phosphate hydrolysis by beryllium (IC50 = 250-300 nM) was observed to the same maximal extent as that seen with lithium in permeabilized SK-N-SH cells, reflecting inhibition of cellular myo-inositol monophosphatase. However, in contrast with that observed with lithium, agonist-induced accumulation of inositol phosphate was not observed with beryllium in permeabilized and non-permeabilized SK-N-SH cells and in rat brain slices. Similar results were obtained in permeabilized SK-N-SH cells when GTP-gamma-S was used as an alternative stimulator of inositol phosphate accumulation. The disparity in the actions of beryllium and lithium suggest that either (1) selective inhibition of myo-inositol monophosphatase does not completely explain the action of lithium on the phosphatidylinositol cycle, or (2) that uncompetitive inhibition of myo-inositol monophosphatase is a necessary requirement to observe functional lithium mimetic activity. |
| Databáze: | OpenAIRE |
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