Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Farnesylthiosalicylic acid (FTS), a synthetic analog of the terminal prenylcysteine present in signaling proteins induces generation of superoxide ions, phospholipase C-driven hydrolysis of inositol lipids and calcium elevation in human neutrophils and DMSO-differentiated HL60 cells. These effects were ascribed to an interaction of the analog with elements responsible for recognition of specific prenylated proteins. The present study demonstrated that in addition to the release of intracellular calcium stores, FTS enhanced entry of Ca(2+) and Mn(2+) from the medium. The biphasic dependence of the influx on the concentration of FTS, as well as its insensitivity to inhibition by PMA and La(3+) suggest that the influx pathway activated by FTS is distinct from the previously described store-operated calcium channels of neutrophils. Consistent with the participation of a cellular membrane component in the interaction, FTS enhanced (45)Ca uptake in neutrophils and neutrophil cell membranes, but not in multilamellar vesicles. To establish specificity of the farnesyl moiety of FTS (C(15)), effects of three other analogs, geranylthiosalicylate, GTS (C(10)), geranylgeranylthiosalicylate, GGTS (C(20)), as well as the carboxymethyl ester FTS-Me on calcium homeostasis and superoxide production were investigated. GGTS dose-dependently elevated [Ca(2+)](i), induced quenching of the 360 nm Fura-2-calcium fluorescence by Mn(2+) and stimulated superoxide release, while GTS and FTS-Me were inactive. These results defined specific structural requirements for the functional interaction of prenylcysteine analogs with myeloid cells.
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PMID:Stimulation of neutrophils by prenylcysteine analogs: Ca(2+) release and influx. 1044

Antipsychotic agents are major drugs for human neuropsychiatric conditions including schizophrenia, mood disorders, Tourette syndrome, and Alzheimer's disease. These drugs are divided in two groups-first-generation/typical and second-generation/atypical-on the basis of their propensity to induce extrapyramidal motor side effects. Furthermore, second-generation antipsychotics have been reported to be superior in addressing cognitive deficits in schizophrenia. Understanding differences between the mechanism of action of first- and second-generation antipsychotic agents thus represents an interesting opportunity for the development of new compounds having better therapeutic action and less side effects. In this issue of Molecular Pharmacology, Fumagalli et al. (p. 1484) report that long-term treatment with the first-generation drug haloperidol interferes with the trafficking of both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate glutamate receptor complexes and associated molecules post-synaptic densities 95 and Ca(2+)calmodulin-dependent protein kinase in the rat frontal cortex. In contrast, the second-generation drug olanzapine did not affect glutamate receptor trafficking. The action of haloperidol on glutamate receptor trafficking in specific brain regions may contribute to the low efficacy of this drug on cognitive deficits and to the development of side effects. Overall, antipsychotics have been shown to act upon multiple signaling mechanisms (e.g., cAMP-protein kinase A, betaArrestin 2-Akt-GSK-3, and phospholipase C-inositol-protein kinase C pathways), mostly by blocking D2-class dopamine receptors (first generation) or D2-class dopamine and 5-HT(2) serotonin receptors (second generation). Identification of specific pathways by which haloperidol affects glutamate receptor trafficking may thus represent an important next step toward the development of better antipsychotic drugs.
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PMID:Messing up with traffic: different effects of antipsychotic agents on glutamate receptor complexes in vivo. 1825 Jan 47