神経伝達物質と修飾物質 Neurotransmitters and modulators
O1-7-4-1 シスタチオニンガンマリアーゼによる硫化水素合成のカルシウム制御 Regulation of H2S production by cystathionine γ-lyase by calcium ○木村英雄1, 三上義礼1,2, 渋谷典広1, 小笠原裕樹3 ○Hideo Kimura1, Yoshinori Mikami1,2, Norihiro Shibuya1, Yuki Ogasawara3 (独）国立精神・神経医療研究センター1, 東京大学　医　薬理2, 明治薬科大3 Dept. Mol. Pharmcol., Natl. Inst. Neurosci., Kodaira, Japan1, Dept. Pharmacol. Univ. Tokyo, Tokyo, Japan2, Meiji Pharmaceut. Univ., Kiyose, Japan3 Hydrogen sulfide (H2S) is recognized as a physiologic mediator produced in a variety of tissues. It is produced by three enzymes, cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3MST). However, the regulation of H2S production by CSE has not well been understood. Here we show that H2S producing activity of CSE is regulated by intracellular Ca2+ concentrations. In the presence of pyridoxal 5'-phosphate (PLP) CSE efficiently produces H2S at the steady-state low Ca2+ concentrations but is suppressed at high Ca2+ concentrations. In the absence of PLP H2S production maintains the suppressed levels at high Ca2+ concentrations and decreased further at low Ca2+ concentrations. These observations suggest that CSE produces H2S at the steady-state in cells and that the production is suppressed when the intracellular Ca2+ concentrations are increased.	O1-7-4-2 D-システインを基質とする新規の硫化水素生産経路 A novel pathway for the production of hydrogen sulfide from D-cysteine in mammalian cells ○渋谷典広1, 小池伸2, 田中真紀子1, 湯浅（石上）磨里1, 木村由佳1, 小笠原裕樹2, 福井清3, 永原則之4, 木村英雄1 ○Norihiro Shibuya1, Shin Koike2, Makiko Tanaka1, Mari Ishigami-Yuasa1, Yuka Kimura1, Yuki Ogasawara2, Kiyoshi Fukui3, Noriyuki Nagahara4, Hideo Kimura1 国立精神・神経医療研究センター・神経研・神経薬理1, 明治薬大・衛生化学2, 徳島大・疾患酵素学研究センター3, 日本医大・アイソトープセンター4 Dept MolPharm, Natl Inst Neurosci, NCNP1, Dept Hygienic Chemistry, Meiji Pharm Univ2, Inst Enzyme Res, Univ of Tokushima3, Isotope Res Center, Nippon Med Sch4 In eukaryotes, hydrogen sulfide (H2S) acts as a signaling molecule and cytoprotectant. H2S is known to be produced from L-cysteine by cystathionine β-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfurtransferase (3MST) coupled with cysteine aminotransferase. Here we report an additional biosynthetic pathway for the production of H2S from D-cysteine involving 3-mercaptopyruvate sulfurtransferase and D-amino acid oxidase. Unlike the L-cysteine pathway, this D-cysteine-dependent pathway seems to operate predominantly in the cerebellum and the kidney. Our study reveals that administration of D-cysteine protects primary cultures of cerebellar neurons from oxidative stress induced by H2O2 and attenuates ischemia-reperfusion injury in the kidney more than L-cysteine. This study presents a novel pathway of H2S production and provides a new therapeutic approach to deliver H2S to specific tissues.
O1-7-4-3 マウス海馬のペリニューロナルネットの発現様式には長軸に沿った差異が存在する Dorsoventral differences in patterns of expression of perineuronal nets in the mouse hippocampus ○神野尚三1, 山田純1, 原田志織1, 関善弘1 ○Shozo Jinno1, Jun Yamada1, Shiori Harada1, Yoshihiro Seki1 九州大学 大学院医学研究院 形態機能形成学分野1 Department of Developmental Molecular Anatomy, Graduate School of Medical Sciences, Kyushu University, Fukuoka1 In the rodent brain, the hippocampus appears grossly as an elongated structure with its longitudinal axis extending in a C-shaped fashion from the septal nuclei of the basal forebrain to the temporal lobe. This septo-temporal alignment of the hippocampus is referred to as the dorsoventral axis. Recent studies substantiate that the dorsal hippocampus is mainly involved in learning and memory, while the ventral hippocampus is responsible for emotion and anxiety-related behaviors. Perineuronal nets (PNNs) were first described by Camillo Golgi in 1882 as the reticular structure that surrounds the cell body and dendrites of neurons and extends along their dendrites. PNNs are specialized substructures of the extracellular matrix, and they are now considered to play a pivotal role in regulation of synaptic plasticity. In this study, we examined the possible dorsoventral difference in patterns of expression of PNNs labeled by Wisteria floribunda agglutinin in the mouse hippocampus. Qualitatively, the distributions of PNNs were rather similar between the dorsal and ventral hippocampus in young adult mice (8 weeks old). However, the labeling intensities of PNN in single cells were significantly higher in the dorsal hippocampus than in the ventral hippocampus. Interestingly, PNNs were definitely present in juvenile mice at postnatal day 14 both in the dorsal and ventral hippocampus. Though, the labeling intensities exhibited no apparent dorsoventral differences at this stage. The patterns of expression of PNNs in the hippocampus of middle-aged mice (12 months old) were generally similar to those seen in young adult mice. In addition, we found that the age-related changes and dorsoventral differences in labeling intensities of parvalbumin, an EF-hand calcium binding protein, were not always linked to those of PNNs. The present results provide novel information to understand the role of PNNs in the hippocampus.	O1-7-4-4 Somatostatin suppresses AMPA currents through a cAMP/PKA signaling pathway in rat retinal ganglion cells ○Qin-Qin Deng1,2,3, Wen-Long Sheng1,2,3, Shi-Jun Weng1,2,3, Xiong-Li Yang1,2,3, Yong-Mei Zhong1,2,3 Institute of Neurobiology, Fudan University, Shanghai, China1, Institutes of Brain Science, Fudan University, Shanghai, China2, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China3 Somatostatin (SRIF) is involved in a variety of physiological functions through activating five subtypes of specific receptors (ssts). In the present work, we investigated the effect of SRIF on AMPA receptor-mediated currents in isolated rat retinal ganglion cells (RGCs) and underlying mechanisms. Whole-cell recording showed that SRIF suppressed AMPA currents of RGCs in a dose-dependent manner. The SRIF effect was mimicked by the sst5 agonist BIM-23206 and reversed by the sst5 antagonist BIM-23056, indicating the involvement of the sst5 receptor, which is consistent with the immunocytochemical result. The effect of SRIF was blocked by intracellular dialysis of GDP-β-S or preincubation with pertussis toxin. The PKA activator cAMP suppressed the AMPA currents, but failed to suppress the currents in the presence of SRIF. In addition, application of the PKA inhibitors Rp-cAMP, H-89 and KT5720 abolished the SRIF-induced suppression. Neither cGMP-PKG nor PC/PI-PLC signaling pathways were likely to be involved because cGMP failed to cause suppression of the AMPA currents, none of the PKG inhibitor KT5823, PC-PLC inhibitor D609 and PI-PLC inhibitor U73122 blocked the SRIF-induced suppression. The SRIF effect was Ca2+-dependent and was abolished when intracellular calcium was chelated by BAPTA. Moreover, calcium imaging showed that SRIF caused a significant elevation of intracellular calcium. The SRIF-induced suppression was blocked by the ryanodine receptor modulators caffeine and ryanodine, but not by the IP3 receptor antagonists heparin and xestospongin-C. We therefore conclude that the increased calcium release from ryanodine-sensitive calcium stores by SRIF via a cAMP/PKA signaling pathway may be responsible for the SRIF-induced suppression of AMPA currents in rat RGCs.

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