日本薬理学雑誌
Online ISSN : 1347-8397
Print ISSN : 0015-5691
ISSN-L : 0015-5691
105 巻, 1 号
選択された号の論文の3件中1~3を表示しています
  • 中西 博, 山本 健二
    1995 年 105 巻 1 号 p. 1-9
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    Recently, attention has been paid to intracellular proteinase functions in relation to the process of neuronal cell death, and defining how they are involved is essential for developing neuroprotective strategies as well as for understanding the pathology of neurodegerative diseases. Several recent articles have outlined the activation and deleterious effect of μ-calpain, a calciumactivated cysteine proteinase, on the cytoskeleton protein network, which is thought to lead to cell death. Furthermore, a marked increase in cathepsins B, L, and D, lysosomal proteinases, and cathepsin E, non-lysosomal aspartic proteinase, in neurons has been shown in the early stage of neuronal degeneration. The increased levels of these lysosomal cathepsins in degenerating neurons are considered to be associated with stimulated autophagy, which occasionally can lead to neuronal cell death. The molecular form of cathepsin E accumulated in affected neurons was different from that of the normal cathepsin E molecule. This unusual molecular form of cathepsin E is likely to be critical for disruption of normal cellular function, possibly culminating in neuronal cell death. The increased level of such proteinases was also found in reactive glial cells. In these cells, cathepsin E was increased as a mature form exclusively in reactive microglial cells, while cathepsins D and G were increased mainly in reactive astrocytes. Overproduction of cathepsins E, D and G in these reactive glial cells may be finally involved in the pathogenesis of neurodegenerative disease.
  • 井上 隆司
    1995 年 105 巻 1 号 p. 11-22
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    Stimulation of excitatory receptors in smooth muscle often leads to the opening of ROCC. These channels exhibit considerable permeability to Ca2+, and they have been regarded as the most probable candidate for the “receptor-operated Ca2+ entry” pathway. The muscarinic receptor ROCC in guinea pig ileum (mROCC) have a unitary conductance of ?? 25pS and are activated through a pertusis toxin-sensitive G protein. mROCC permeate Ca2+ and Ba2+ several fold more preferably than monovalent cations, and they are inhibited by various types of K channel blockers, diphenylamine-2-carboxylate derivatives and even by nicardipine and D-600 at high concentrations. mROCC are efficiently regulated by various physiological factors including the membrane potential, intracellular Ca2+ concentration, external pH and osmolarity. The effective ranges of these factors span their dynamic ranges under physiological conditions. In addition to these properties, mROCC have several sites sensitive to external polyvalent cations. The α1-adrenergic receptor ROCC in rabbit portal vein resemble mROCC in many respects, e.g., the unitary conductance, ionic selectivity, activation kinetics, sensitivity to polyvalent cations and voltage-dependence. These complex characteristics of ROCC suggest that they play other roles in addition to being just a passive cation permeable pore in agonist-mediated Ca2+ mobilization in smooth muscle.
  • Kiyokazu OGITA
    1995 年 105 巻 1 号 p. 23-33
    発行日: 1995年
    公開日: 2007/02/06
    ジャーナル フリー
    A series of investigations has been made to analyze the receptive mechanisms for signals mediated by an N-methyl D-aspartic acid (NMDA)-sensitive subclass of brain excitatory amino acid receptors. Treatment of synaptic membranes with a low concentration of Triton X-100 induced a drastic disclosure of NMDA-sensitive [3H] glutamic acid binding without affecting the NMDAinsensitive populations. In these Triton-treated membranes, binding of [3H] glycine (Gly) was displaced by D-serine and D-alanine, but not by strychnine. These membrane preparations were also useful for detecting the binding of noncompetitive blockers to open NMDA channels in a manner highly sensitive to potentiation by NMDA, Gly and the polyamine spermidine. Comparative studies on the binding of agonist and antagonist ligands in different central regions suggested the possible heterogeneity of the NMDA, Gly and ionophore domains. By screening more than 1000 compounds, the binding of noncompetitive blockers was completely abolished by the addition of 6, 7dichloroquinoxaline-2, 3-dione, which was revealed to be a selective antagonist for the Gly domain. Binding studies using the aforementioned radioligands gave rise to the idea that both reduced and oxidized glutathione could be endogenous agonists for the NMDA domain. An i.c.v. injection of NMDA led to a marked potentiation of DNA binding activities of particular transcription factors in a manner sensitive to antagonism by antagonists at the respective domains. These results suggest that NMDA signals are indeed transduced from cell surfaces into nuclei to express nuclear transcription factors through the NMDA-sensitive subclass that is a receptor ionophore complex consisting of at least 4 different constituents including the NMDA, Gly, polyamine and ionophore domains.
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