h-89 and 1-(5-isoquinolinylsulfonyl)-3-methylpiperazine

h-89 has been researched along with 1-(5-isoquinolinylsulfonyl)-3-methylpiperazine* in 2 studies

Other Studies

2 other study(ies) available for h-89 and 1-(5-isoquinolinylsulfonyl)-3-methylpiperazine

ArticleYear
Extracellular Ca2+ sensitivity of mGluR1alpha induces an increase in the basal cAMP level by direct coupling with Gs protein in transfected CHO cells.
    Receptors & channels, 2000, Volume: 7, Issue:2

    We previously reported that the metabotropic glutamate receptor R1alpha (mGluR1alpha) can be activated not only by applying glutamate but also by raising extracellular Ca2+ (Ca2+o) concentration, and that the constant stimulation by Ca2+o causes morphological change of transfected Chinese Hamster Ovary (CHO) cells (Kubo Y Miyashita T and Murata Y (1998) Science 279, 1722-1725). The physiological role of the Ca2+o-sensing function of mGluR1alpha, however, is not fully clear yet, especially because Ca2+ is constitutively present in the extracellular space unlike other neurotransmitters. In this work, we aimed to elucidate the physiological significance of the Ca2+o-sensing function of mGluR1alpha. The effect of mGluR1alpha activation by Ca2+o on the morphological change of CHO cells was mimicked by forskolin. The effect of mGluR1alpha activation on the morphological change was suppressed by the inhibitors of adenylate cyclase, protein kinase A (PKA) and MAP kinase kinase (MAPKK), and the effect of forskolin was also decreased by the inhibitors of PKA and MAPKK. These results demonstrate the involvement of cAMP, PKA, MAPKK, MAPK pathway in the morphological change. We actually confirmed that the Ca2+o stimulation of mGluR1alpha increased the basal cAMP level of transfected CHO cells. This increase in cAMP was observed even when only the membrane fraction of mGluR1alpha transfected CHO cells were used, and the increase was inhibited by anti-Gs alpha antibody. Taken together, we concluded that the Ca2+o-sensing function of mGluR1alpha and the continuous stimulation by Ca2+o caused the increase in the basal cAMP level by direct coupling with Gs, and triggered the subsequent activation of PKA, MAPKK, and MAPK cascade which resulted in the morphological change of transfected CHO cells.

    Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Actins; Animals; Calcium; Cell Size; CHO Cells; Colforsin; Cricetinae; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Enzyme Inhibitors; Flavonoids; Fluorescent Dyes; Glutamic Acid; GTP-Binding Protein alpha Subunits, Gs; Isoquinolines; MAP Kinase Signaling System; Protein Kinase C; Receptors, Metabotropic Glutamate; Signal Transduction; Sulfonamides; Tetradecanoylphorbol Acetate; Transfection; Type C Phospholipases

2000
Crystal structures of catalytic subunit of cAMP-dependent protein kinase in complex with isoquinolinesulfonyl protein kinase inhibitors H7, H8, and H89. Structural implications for selectivity.
    The Journal of biological chemistry, 1996, Oct-18, Volume: 271, Issue:42

    The discovery of several hundred different protein kinases involved in highly diverse cellular signaling pathways is in stark contrast to the much smaller number of known modulators of cell signaling. Of these, the H series protein kinase inhibitors (1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7), N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide (H8) N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89)) are frequently used to block signaling pathways in studies of cellular regulation. To elucidate inhibition mechanisms at atomic resolution and to enable structure-based drug design of potential therapeutic modulators of signaling pathways, we determined the crystal structures of corresponding complexes with the cAPK catalytic subunit. Complexes with H7 and H8 (2.2 A) and with H89 (2.3 A) define the binding mode of the isoquinoline-sulfonamide derivatives in the ATP-binding site while demonstrating effects of ligand-induced structural change. Specific interactions between the enzyme and the inhibitors include the isoquinoline ring nitrogen ligating to backbone amide of Val-123 and an inhibitor side chain amide bonding to the backbone carbonyl of Glu-170. The conservation of the ATP-binding site of protein kinases allows evaluation of factors governing general selectivity of these inhibitors among kinases. These results should assist efforts in the design of protein kinase inhibitors with specific properties.

    Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Binding Sites; Casein Kinase II; Casein Kinases; Cattle; Crystallography, X-Ray; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP-Dependent Protein Kinases; Enzyme Inhibitors; Glycine; Isoquinolines; Myosin-Light-Chain Kinase; Protein Conformation; Protein Kinase C; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Sulfonamides

1996