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Volume 114, Issue 3
Displaying 1-9 of 9 articles from this issue
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Yusuke NAKAMURA1999 Volume 114 Issue 3 Pages 126-130
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSThe human genome project is considered to be the most important project in biology and medicine. The discovery of an entire human genes through this project should revolutionize biological medicine including molecular diagnosis of various diseases and development of novel treatment. The entire genome DNA sequence is expected to be completed by 2003, and 90% of the genes will be identified by 2001. The information will accelerate discovery of genes susceptible to or causing various diseases and contribute to screening of novel drugs that target these disease-gene products. In addition, the field of “phamacogenetics"” will become more important. Phamacogenetic studies focusing on inherited variations in drug metabolism and polymorphisms in drug metabolisms of the genes encoding drug-metabolizing enzymes are also very important to determine an appropriate dose of certain drugs to obtain the maximum effect and avoid serious toxicity. In this regard, the recent world-wide effort of the SNP (single nucleotide polymorphism) project in which scientists attempt to discover 100, 000 genetic variations in our genome will generate very variable resources. In this review, I will be describing the recent progress and future direction of human genome analysis and its impact on medicine and pharmacology.View full abstractDownload PDF (5511K) -
Hiroshi OKAMOTO1999 Volume 114 Issue 3 Pages 131-139
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSGlucose induces an increase in the intracellular Ca2+ concentration in pancreatic β-cells to secrete insulin. CD38 exists in β-cells and has both ADP-ribosyl cyclase, which catalyzes the formation of cyclic ADP-ribose (cADPR) from NAD+, and cADPR hydrolase, which converts cADPR to ADP-ribose. ATP, produced by glucose metabolism, competes with cADPR for the binding site, Lys-129, of CD38, resulting in the inhibition of the hydrolysis of cADPR and thereby causing cADPR accumulation in β-cells. cADPR then binds to FK506-binding protein 12.6 (FKBP12.6) in the islet type of the ryanodine receptor (RyR), dissociating the binding protein from RyR to induce the release of Ca2+ from the endoplasmic reticulum. Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) phosphorylates RyR to sensitize and activate the Ca2+ channel. Ca2+, released from the RyR, further activates CaM kinase II and amplifies this process. Thus, cADPR acts as a second messenger for Ca2+ mobilization to secrete insulin. The novel mechanism of insulin secretion described above is different from the conventional hypothesis in which Ca2+ influx from extracellular sources plays a role in insulin secretion by glucose. Furthermore, many physiological and pathological phenomena in various tissues and cells such as cardiac muscles, cerebellum, neuronal cells, pancreatic acinar cells, alveolar macrophages and immune B-cells become understandable in terms of “the CD38-cADPR signaling system” that sometimes acts in cooperation with other signal systems.View full abstractDownload PDF (10781K) -
Kazuo WATANABE1999 Volume 114 Issue 3 Pages 141-148
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSProspects for future development in the field of gastrointestinal pharmacology were briefly discussed on the base of the present progress in our own research on animal models of gastric ulcer and the mechanism of gastric acid secretion. We established a few novel methods to induce extensive ulceration restricted to the gastric antral area in rats by a combination of drug-induced vagal stimulation with necrotizing agents or anti-inflammatory drugs, as well as with ammonia in relation to the etiological role of Helicobacter pilori. In these models, it was found that the gastric antral area become sensitive to mucosal aggression under vagal stimulation and refeeding after starvation and that the mucosal primary afferent nervous system was involved in the integration of gastric mucosal defense mechanisms. Among many experimental gastric ulcer models, the gastric antral ulcer is important for future study because of its unique analogy with human ulcer in its location of incidence and pathology. We also established methods to measure gastric acid secretion in the isolated gastric mucosa or whole stomach of rat or mouse, as well as acid secretion in anesthetized rats. By using these methods, the signal transduction route of vagus nerve stimulation to parietal cells was studied. The importance of mediation of enterochromaffin cells in gastric acid secretion was clearly confirmed. In the studies on receptor mechanisms in the central nervous system regulating gastric acid secretion, critical roles of GABA, barbiturate, glutamate, neurosteroids and opioid receptors were clarified. From these results, several remaining problems were suggested and these must be resolved in future research.View full abstractDownload PDF (8592K) -
Yasuo MORI, Takaharu OKADA, Shunichi SHIMIZU1999 Volume 114 Issue 3 Pages 149-160
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSReceptor-activated Ca2+ channels (RACC) are triggered in response to activation of G protein-coupled receptors or tyrosine kinase-coupled receptors. RACCs, together with voltage-dependent Ca2+ channels, form physiologically the most important Ca2+ influx pathways, being highly diverged in activation mechanisms and Ca2+ permeability. Characterization of mammalian homologues of Drosophila TRP proteins has been an important clue for understanding molecular mechanisms underlying receptor-activated Ca2+ influx in vertebrate cells. Recent issues have been whether any members of the TRP family form capacitative Ca2+ entry (CCE) channels activated by release of Ca2+ from internal stores and their depletion. We have isolated cDNAs that encode seven mouse TRP homologues, TRP1-7. TRP homologues are distributed differently among tissues, although they are all abundant in the brain. Functional characterization of TRP proteins recombinantly expressed in HEK cells indicate that TRP5 is highly permeable to Ca2+, while TRP3 and 7 are non-selective cation channels. The results demonstrate that TRP3, 5, 7 are capable of generating Ca2+ currents after desensitization of the stimulated G-protein-coupled receptors and replenishment of stores, suggesting that store depletion is not necessary to maintain activity of the TRP homologues. Ca2+ positively regulates TRP channels through Ca2+-calmodulin pathways, but via different Ca2+-calmodulin-dependent enzymes. Thus, activation of TRP channels is not tightly coupled with store depletion as CCE, suggesting that CCE (or CRAC) channels are molecular entities separate from TRP.View full abstractDownload PDF (13232K) -
Kyoko OMORI, Chiyoko INAGAKI, Masashi SASA1999 Volume 114 Issue 3 Pages 161-168
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSFor the development of new drugs for hitherto untreatable epilepsy, it is necessary to clarify the basic pathophysiology involved in such epileptic seizures and find the target site. This review focused on molecular events related to the expression and expansion of the epileptic focus which are the target of novel antiepileptics. Immediate early genes such as c-fos followed by expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have been evidenced as initial important phenomena in the cascade of molecular systems that develop and complement the transient neuronal excitation to long-term neuronal plasticity. Non-receptor type tyrosine kinase Fyn in the Src family has been suggested to promote kindling development via tyrosine phosphorylation of the NMDA-receptor subunit, NR2B. The cause of abnormality in the inhibitory system is induced by lowering of glutamate-dependent GABA release in the epileptic focus within the hippocampus in human temporal epilepsy. This is probably attributed to a decrease in GABA transporters. Regarding abnormality of the excitatory system, there is an increase in glutamate release prior to convulsive seizures, an enhancement of NMDA receptor responsiveness and high levels of AMPA receptors related to convulsion after completion of kindling. In gene analysis of human familiar epilepsy, abnormalities and point mutations have recently been found in the following genes: KCNQ2 and KCNQ3, coding for K+ channels; CHRNA4 of the nicotinic receptor subunit α4; and the cystatin B gene. In epilepsy model mice, EL mice with several gene mutations known to be involved in the seizures, the El-1 gene contains an abnormality of the ceruloplasmin gene. SER (spontaneously epileptic rat: zi/zi, tm/tm), a double mutant, manifests a deletion of the region containing the aspartoacylase gene related to the tm gene. Since an increase in N-acetyl-L-aspartate (NAA) is observed in the SER brain, NAA may serve to evoke seizures.View full abstractDownload PDF (9348K) -
Kazuhiko YANAI1999 Volume 114 Issue 3 Pages 169-178
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSNeuroimaging is a powerful and innovative tool for studying the pathology of psychiatric and neurological diseases and, more recently, for studying the drugs used in their treatment. Technological advances in imaging have made it possible to noninvasively extract information from the human brain regarding a drug's mechanism and site of action. Until now, our understanding of human brain pharmacology has depended primarily on indirect assessments or models derived from animal studies. However, the advent of multiple techniques for human brain imaging allows researchers to focus directly on human pharmacology and brain function. In this review article, our PET studies on the histaminergic neuron system were presented as an example. We have developed and used the PET techniques for 10 years in order to examine the H1 receptors in the living human brain. This review outlines available PET techniques and examines how these various methods have already been applied to the drug development process and neuropharmacology in the living human brain.View full abstractDownload PDF (12024K) -
Kazuya TANIGUCHI, Shunnji KAYA, Takeshi YOKOYAMA, Kazuhiro ABE1999 Volume 114 Issue 3 Pages 179-184
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSSince the discovery of Na/K-ATPase by Skou, the mechanism of Na K-dependent ATP hydrolysis and Na and K transport has been extensively studied. The hydrolysis appears to occur sequentially via the Na-Enzyme-ATP complex (NaE1ATP), ADP-sensitive phosphoenzyme (NaE1P), the K-sensitive phosphoenzyme (E2P) and the K-occluded enzyme (KE2), known the Post-Albers mechanism, in a protomer or diprotomer that consists of α- and β-chains. The tetrameric nature of the enzyme such as a quarter, half, third to fourth and full site reactivity and the visualization by electron microscopy show direct biochemical evidence for the presence of a tetraprotomer structure of Na/K-ATPase during ATP hydrolysis. ATP binding is followed by two parallel paths, which occur at each of the two half sites for phosphorylation-dephosphorylation, and direct ATP hydrolysis via (NaE1P : E·ATP)2, (E2P : E·ATP : E2P : E·ADP/Pi) and (KE2 : E·ADP/Pi)2, respectively. The sequential formation of E2P from NaE1P and KE2 from E2P is accompanied by, respectively, hydrolysis of half of the TCA-labile bound ATP to ADP/Pi and of another half of the bound ATP to ADP/Pi. All reaction intermediates detectable in the Post-Albers scheme bind ATP and/or ADP/Pi.View full abstractDownload PDF (7550K) -
Yoshihiko CHIBA, Miwa MISAWA1999 Volume 114 Issue 3 Pages 185-190
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSNonspecific airway hyperresponsiveness (AHR) is a common feature of allergic bronchial asthmatics, but the underlying mechanism(s) of AHR have yet to be elucidated. The importance of AHR in the pathogenesis of asthma has been suggested by its relevance to the severity of this disease. There is thus a need to understand the underlying mechanisms of AHR for the sake of asthma therapy. In the present minireview, we discussed the involvement of the augmented agonist-induced Ca2+ sensitization of airway smooth muscle contraction in the pathogenesis of AHR. Treatment with acetylcholine (ACh) of a β-escinpermeabilized intrapulmonary bronchial smooth muscle of the rat induced a stronger contractile force even when the Ca2+ concentration was clamped at 1 μM. The ACh-induced Ca2+ sensitization of myofilaments was found to be significantly greater in antigen-induced airway hyperresponsive rats than in control rats. The ACh-induced Ca2+ sensitization was completely blocked by treatment with Clostridium botulinum C3 exoenzyme, an inactivator of the Rho family proteins. Moreover, the protein level of RhoA in the intrapulmonary bronchi was demonstrated to be significantly increased in the airway hyperresponsive rats. Thus, the increased airway smooth muscle contractility observed in asthmatics may be related to the augmented agonist-induced, Rho-mediated Ca2+ sensitization of myofilaments.View full abstractDownload PDF (6426K) -
Shigeo KASUGA, Mitsuyasu USHIJIMA, Naoaki MORIHARA, Yoichi ITAKURA, Yo ...1999 Volume 114 Issue 3 Pages 191-197
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSThe effect of aged garlic extract (AGE) on stress induced hyperglycemia was investigated using the immobilization stress model in mice. After the exposure to immobilization stress for 16 hr per day for 2 consecutive days, the adrenal glands of the mice hypertrophied, and their serum glucose level and corticosterone secretion became elevated, but insulin secretion did not change. These results suggest that the elevation of serum glucose was probably due to the stimulation of the pituitary-adrenocortical axis by the stress. Pretreatment of AGE (5 and 10 ml/kg, p.o.) significantly prevented adrenal hypertrophy, hyperglycemia and elevation of corticosterone, but did not alter serum insulin level. The efficacy of AGE was the same as that of diazepam (5 mg/kg, p.o.). From these results, it is suggested that AGE may prevent stress-induced hyperglycemia, which is the risk of suffering from diabetes mellitus and its progression.View full abstractDownload PDF (6972K)
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