TAILIEUCHUNG - Báo cáo khoa học: Characterization of inhibitors of phosphodiesterase 1C on a human cellular system

Different inhibitors of the Ca 2+ ⁄calmodulin-stimulated phosphodiester-ase 1 family have been described and used for the examination of phospho-diesterase 1 in cellular, organ or animal models. However, the inhibitors described differ in potency and selectivity for the different phosphodiester-ase family enzymes, and in part exhibit additional pharmacodynamic actions. | ễFEBS Journal Characterization of inhibitors of phosphodiesterase 1C on a human cellular system Torsten R. Dunkern and Armin Hatzelmann Biochemistry 2 Inflammation ALTANA Pharma AG Member of the Nycomed Group Konstanz Germany Keywords glioblastoma cell line 8-methoxymethyl-3-isoabutyl-1-methylxanthine phosphodiesterase 1C SCH51866 vinpocetine Correspondence T. R. Dunkern Department of Biochemistry Inflammation RPR B2 ALTANA Pharma AG Member of the Nycomed Group Byk-Gulden-Str. 2 78467 Konstanz Germany Fax 49 7531 84 2712 Tel 49 7531 84 3121 E-mail Received 25 April2007 revised 17 July 2007 accepted 19 July 2007 doi Different inhibitors of the Ca2 calmodulin-stimulated phosphodiesterase 1 family have been described and used for the examination of phosphodiesterase 1 in cellular organ or animal models. However the inhibitors described differ in potency and selectivity for the different phosphodiesterase family enzymes and in part exhibit additional pharmacodynamic actions. In this study we demonstrate that phosphodiesterase 1C is expressed in the human glioblastoma cell line A172 with regard to mRNA protein and activity level and that lower activities of phosphodiesterase 2 phosphodiesterase 3 phosphodiesterase 4 and phosphodiesterase 5 are also present. The identity of the phosphodiesterase 1C activity detected was verified by downregulation of the mRNA and protein through human phosphodiesterase 1C specific small interfering RNA. In addition the measured Km values cAMP pM cGMP pM are characteristic of phosphodiesterase 1C. We demonstrate that treatment with the Ca2 ionophore ionomycin increases intracellular Ca2 in a concentration-dependent way without affecting cell viability. Under conditions of enhanced intracellular Ca2 concentration a rapid increase in cAMP levels caused by the adenylyl cyclase activator forskolin was abolished indicating the involvement of Ca2 -activated .

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