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Volume 119 (2002)
- Issue 6 Pages 319-
- Issue 5 Pages 273-
- Issue 4 Pages 201-
- Issue 3 Pages 135-
- Issue 2 Pages 65-
- Issue 1 Pages 7-
Volume 119, Issue 4
Displaying 1-8 of 8 articles from this issue
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Reviews: Genetically Engineered Mice as a Tool for Pharmacological Studies
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Fumitaka USHIKUBI, Shuh NARUMIYAArticle type: Reviews
2002 Volume 119 Issue 4 Pages 201-207
Published: 2002
Released on J-STAGE: January 21, 2003
JOURNAL FREE ACCESSThe actions of prostanoids in various physiological and pathophysiological conditions have been examined using mice lacking the prostanoid receptors. PGD2 was found to be a mediator of allergic asthma. Prostaglandin (PG) I2 worked not only as a mediator of inflammation but also as an antithrombotic and cardio-protective agent. Several important actions of PGE2 are brought out via the PGE2-receptor subtype EP3; PGE2 participated in the regulation of platelet function, and it worked as a mediator of febrile responses to both endogenous and exogenous pyrogens. These novel findings on the roles of the prostanoids would contribute to the development of drugs targeting the prostanoid receptors.
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Hiroshi YAMAZAKI, Tetsuya KAMATAKIArticle type: Reviews
2002 Volume 119 Issue 4 Pages 208-212
Published: 2002
Released on J-STAGE: January 21, 2003
JOURNAL FREE ACCESSMultiple forms of cytochrome P450 play important roles in metabolic activation of a variety of environmental procarcinogens. Large species differences in substrate specificities between experimental animals and humans are critical factors in evaluation of chemical safety. To study the role of human P450s in genotoxic activation of environmental chemicals, transgenic bacteria expressing both human P450s and P450 reductase have been developed for the mutagenicity test. Mice lacking CYP1A2, and CYP1B1, and CYP2E1 were prepared to investigate the mechanism of procarcinogen activation in vivo. The first human transgenic animals were mice carrying human fetus-specific CYP3A7. Using these transgenic mice, mutagenic activation of a natural mycotoxin, aflatoxin B1, catalyzed by CYP3A7 in vivo was demonstrated. This observation was clear in extrahepatic tissues that did not express mouse CYP3A enzymes. In conclusion, P450s are key factors involved in metabolic activation of environmental procarcinogens for their biological actions.
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Yukihiro NODA, Toshitaka NABESHIMAArticle type: Reviews
2002 Volume 119 Issue 4 Pages 213-217
Published: 2002
Released on J-STAGE: January 21, 2003
JOURNAL FREE ACCESSWe investigated the possible mechanisms of development of latent learning and morphine dependence by the methods of behavioral pharmacology and confirmed them by using mutant mice. The heterozygous mice for the tyrosine hydroxylase (TH) gene and for the cyclic AMP (cAMP) response element binding protein (CREB) binding protein (CBP) gene showed the impairment of latent learning in the water finding task, and these mice did not develop morphine dependence. The spatial learning and hippocampal long-term potentiation (LTP) were normal in the both mutants. TH heterozygous mice showed a reduction of high K+-evoked noradrenaline release in the frontal cortex measured by the microdialysis technique and of cAMP content in the brain. In conclusion, the results of mutant mice suggest that the alternation of catecholamine biosynthesis and cAMP signal pathways may play a key role in development of latent learning and morphine dependence, and they furthermore show that the expression of genes mediated by phosphorylated CREB may be involved in the development of latent learning and morphine dependence.
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Koji ICHIKAWA, Tetsuo NODA, Yasuhiro FURUICHIArticle type: Reviews
2002 Volume 119 Issue 4 Pages 219-226
Published: 2002
Released on J-STAGE: January 21, 2003
JOURNAL FREE ACCESSThe list of human RecQ helicase comprises RecQ1, BLM (Bloom syndrome), WRN (Werner syndrome), RTS (Rothmund-Thomson syndrome), and RecQ5. Of these, the defective BLM, WRN, and RTS helicases are responsible for distinct but overlapping clinical features suggesting premature aging and an enhanced risk of cancer, which apparently stems from chromosomal instability in the cells of tissues and organs where expression of the helicase genes are specified. In an effort to obtain an animal model for these diseases, we performed gene target experiments to generate the WRN and RTS knockout mice.
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Yoshiko TOKUTOMI, Shigeko TORIHASHI, Naofumi TOKUTOMI, Katsuhide NISHIArticle type: Reviews
2002 Volume 119 Issue 4 Pages 227-234
Published: 2002
Released on J-STAGE: January 21, 2003
JOURNAL FREE ACCESSThe origin of rhythmicity in gastrointestinal motility was long thought to involve the activity of interstitial cells of Cajal (ICC) that locate in close association with enteric neurons and smooth muscle cells. We have demonstrated that significant decrease in the number of cells immunopositive to c-Kit, a type of tyrosine kinase receptor, in the gastrointestinal tract of mice mutated at the W/c-kit locus and BALB/c mice administered with neutralizing c-Kit antibody leads to the impaired autonomic motility of the gastrointestinal tract. It is also demonstrated that ICC express c-kit which plays important roles in development and maintenance of the ICC network in the gastrointestinal tract. ICC, derived from mesenchymal cells, are classified into smooth muscle type and fibroblast type by their morphology and tissue location. The ligand for c-Kit, Sl factor (SLF), has shown to be expressed in enteric neurons and gastrointestinal smooth muscle cells. Studies with mutant mice and transgenic mice have suggested that functional c-Kit/SLF is required for the differentiation and proliferation of ICC as pacemakers and mediators of neural regulation in gastrointestinal motility. Here we review the genetic basis of autonomic gastrointestinal motility and the pathophysiological models.
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Review
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Toshihiko MOMIYAMAArticle type: Review
2002 Volume 119 Issue 4 Pages 235-240
Published: 2002
Released on J-STAGE: January 21, 2003
JOURNAL FREE ACCESSIt is well established that neurotransmitter release is triggered by Ca2+ entry into the presynaptic terminals through voltage-dependent Ca2+ channels. In the mammalian central nervous system, multiple types of Ca2+ channels including N-type, P/Q-type and other types mediate fast synaptic transmission. Electrophysiological studies using type-specific antagonists for Ca2+ channels have estimated the relative contribution of N-, P/Q- and other types of Ca2+ channels in excitatory and inhibitory synaptic transmission in the hippocampus, cerebellum, spinal cord, brain stem, and striatum. A recent study has demonstrated that activation of presynaptic dopamine D2-like receptors selectively block N-type Ca2+ channels to reduce GABA release onto cholinergic interneurons in the rat striatum. In addition, it has been recently clarified that the contribution of N-type Ca2+ channels to synaptic transmission is restricted to the early postnatal period at synapses in auditory brain stem, cerebellum, or thalamus. Advanced morphological studies are necessary for the further understanding of the subcellular localization of each subtype of Ca2+ channels and receptors modulating the transmitter release through Ca2+ channel activity in relation to the release sites in the presynaptic terminals.
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Technical Note
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Takashi KANEMATSU, Masato HIRATAArticle type: Technical Note
2002 Volume 119 Issue 4 Pages 241-246
Published: 2002
Released on J-STAGE: January 21, 2003
JOURNAL FREE ACCESSAnalysis of protein-protein interaction is one of the powerful methods for elucidating the new functions of functionally unknown proteins. Using this approach, we isolated two proteins interacting with PRIP-1, which was isolated as a new Ins(1,4,5)P3 binding protein from brain. One was protein phosphatase 1 catalytic subunit (PP1c) and the other was GABARAP (GABAA-receptor-associated protein). The region of PRIP-1 responsible for their interaction was the site preceding to the pleckstrin homology domain of PRIP-1 for PP1c and the EF-hand motifs of PRIP-1 for GABARAP, which were determined by β-galactosidase assay of yeast two-hybrid system. The association between PRIP-1 and PP1c was confirmed in vitro by a pull-down assay, a far-western assay, an immunoprecipitation analysis and a surface plasmon resonance analysis. The interaction of PRIP-1 with PP1c resulted in inhibition of the catalytic activity of PP1c in a PRIP-1 concentration-dependent manner. The association between PRIP-1 and GABARAP was also confirmed by a pull-down assay, and we found that PRIP-1 competitively inhibited the binding of the γ2 subunit of the GABAA receptor to GABARAP in vitro. Our electrophysiological and behavioral analysis of PRIP-1 knockout mice revealed that PRIP-1 is essential for the function of GABAA receptors, especially in response to the agents acting on the γ2 subunit.
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Review on New Drug
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Yosuke MURATA, Osamu SUGIMOTOArticle type: Review on New Drug
2002 Volume 119 Issue 4 Pages 247-258
Published: 2002
Released on J-STAGE: January 21, 2003
JOURNAL FREE ACCESSToday, bronchial asthma is considered as a chronic inflammatory disease of the airway. It has been revealed that various chemical mediators are involved in the onset of bronchial asthma. Among them, particularly, the peptide leukotrienes, LTC4, LTD4 and LTE4, have been known to play a pathophysiological important role in asthma. Zafirlukast binds to the CysLT1 receptors competitively with these peptide leukotrienes and inhibited peptide leukotriene-induced constriction of isolated guinea pig trachea and lung parenchyma and isolated human bronchi. Zafirlukast also demonstrated dose-dependent inhibition of LTD4-induced dyspnea in guinea pigs in vivo. Zafirlukast demonstrated preventive and alleviating effects on LTD4- and ovalbumin-induced decrease in the lung function. Zafirlukast also displayed inhibitory effects on LTD4-induced eosinophil infiltration into airway tissues and bronchial edema. In sheep naturally allergic to Ascaris suum antigen, zafirlukast exhibited inhibitory effects on Ascaris suum antigen-induced immediate and late type airway constriction and increase in airway hypersensitivity. In clinical pharmacology studies, zafirlukast inhibited LTD4- or allergen-induced airway constriction and exercise-induced reduction of the pulmonary function. It also prevented onset of methacholine-induced airway hyperresponsiveness. Furthermore, good efficacy of zafirlukast was confirmed in clinical trials in adult bronchial asthma patients. As above, zafirlukast is effective for treatment of bronchial asthma, which is attributed to its peptide leukotriene antagonistic action.
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