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| 1.
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Higashida, Haruhiro ; Salmina, Alla B. ; Olovyannikova, Raissa Ya ; Hashii, Minako ; Yokoyama, Shigeru ; Koizumi, Keita ; Jin, Duo ; Liu, Hong-Xiang ; Lopatina, Olga ; Amina, Sarwat ; Mohammad, Saharul Islam ; Huang, Jian-Jun ; Noda, Mami
概要:
金沢大学大学院医学系研究科脳細胞分子学<br />β-NAD+ is as abundant as ATP in neuronal cells. β-NAD+ functions not only as a coenzyme but als
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o as a substrate. β-NAD+-utilizing enzymes are involved in signal transduction. We focus on ADP-ribosyl cyclase/CD38 which synthesizes cyclic ADP-ribose (cADPR), a universal Ca2+ mobilizer from intracellular stores, from β-NAD+. cADPR acts through activation/modulation of ryanodine receptor Ca2+ releasing Ca2+ channels. cADPR synthesis in neuronal cells is stimulated or modulated via different pathways and various factors. Subtype-specific coupling of various neurotransmitter receptors with ADP-ribosyl cyclase confirms the involvement of the enzyme in signal transduction in neurons and glial cells. Moreover, cADPR/CD38 is critical in oxytocin release from the hypothalamic cell dendrites and nerve terminals in the posterior pituitary. Therefore, it is possible that pharmacological manipulation of intracellular cADPR levels through ADP-ribosyl cyclase activity or synthetic cADPR analogues may provide new therapeutic opportunities for treatment of neurodevelopmental disorders. © 2007.
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| 2.
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論文
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Zhong, Jing ; Amina, Sarwat ; Liang, Mingkun ; Akther, Shirin ; Yuhi, Teruko ; Nishimura, Tomoko ; Tsuji, Chiharu ; Tsuji, Takahiro ; Liu, Hong-Xiang ; Hashii, Minako ; Furuhara, Kazumi ; Yokoyama, Shigeru ; Yamamoto, Yasuhiko ; Okamoto, Hiroshi ; Zhao, Yong Juan ; Lee, Hon Cheung ; Tominaga, Makoto ; Lopatina, Olga ; Higashida, Haruhiro
概要:
Hypothalamic oxytocin (OT) is released into the brain by cyclic ADP-ribose (cADPR) with or without depolarizing stimulat
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ion. Previously, we showed that the intracellular free calcium concentration ([Ca2+]i) that seems to trigger OT release can be elevated by β-NAD+, cADPR, and ADP in mouse oxytocinergic neurons. As these β-NAD+ metabolites activate warm-sensitive TRPM2 cation channels, when the incubation temperature is increased, the [Ca2+]i in hypothalamic neurons is elevated. However, it has not been determined whether OT release is facilitated by heat in vitro or hyperthermia in vivo in combination with cADPR. Furthermore, it has not been examined whether CD38 and TRPM2 exert their functions on OT release during stress or stress-induced hyperthermia in relation to the anxiolytic roles and social behaviors of OT under stress conditions. Here, we report that OT release from the isolated hypothalami of male mice in culture was enhanced by extracellular application of cADPR or increasing the incubation temperature from 35°C to 38.5°C, and simultaneous stimulation showed a greater effect. This release was inhibited by a cADPR-dependent ryanodine receptor inhibitor and a nonspecific TRPM2 inhibitor. The facilitated release by heat and cADPR was suppressed in the hypothalamus isolated from CD38 knockout mice and CD38-or TRPM2-knockdown mice. In the course of these experiments, we noted that OT release differed markedly between individual mice under stress with group housing. That is, when male mice received cage-switch stress and eliminated due to their social subclass, significantly higher levels of OT release were found in subordinates compared with ordinates. In mice exposed to anxiety stress in an open field, the cerebrospinal fluid (CSF) OT level increased transiently at 5 min after exposure, and the rectal temperature also increased from 36.6°C to 37.8°C. OT levels in the CSF of mice with lipopolysaccharide-induced fever (+0.8°C) were higher than those of control mice. The TRPM2 mRNA levels and immunoreactivities increased in the subordinate group with cage-switch stress. These results showed that cADPR/CD38 and heat/TRPM2 are co-regulators of OT secretion and suggested that CD38 and TRPM2 are potential therapeutic targets for OT release in psychiatric diseases caused by social stress. © 2016 Zhong, Amina, Liang, Akther, Yuhi, Nishimura, Tsuji, Tsuji, Liu, Hashii, Furuhara, Yokoyama, Yamamoto, Okamoto, Zhao, Lee, Tominaga, Lopatina and Higashida.
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| 3.
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Higashida, Haruhiro ; Yokoyama, Shigeru ; Kikuchi, Mitsuru ; Munesue, Toshio
概要:
Here, we review the functional roles of cyclic ADP-ribose and CD38, a transmembrane protein with ADP-ribosyl cyclase act
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ivity, in mouse social behavior via the regulation of oxytocin (OXT) release, an essential component of social cognition. Herein we describe data detailing the molecular mechanism of CD38-dependent OXT secretion in CD38 knockout mice. We also review studies that used OXT, OXT receptor (OXTR), or CD38 knockout mice. Additionally, we compare the behavioral impairments that occur in these knockout mice in relation to the OXT system and CD38. This review also examines autism spectrum disorder (ASD), which is characterized by social and communication impairments, in relation to defects in the OXT system. Two single nucleotide polymorphisms (SNPs) in the human CD38 gene are possible risk factors for ASD via inhibition of OXT function. Further analysis of CD38 in relation to the OXT system may provide a better understanding of the neuroendocrinological roles of OXT and CD38 in the hypothalamus and of the pathophysiology of ASD. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. © 2011 Elsevier Inc.
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| 4.
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Higashida, Haruhiro ; Yokoyama, Shigeru ; Munesue, Toshio ; Kikuchi, Mitsuru ; Minabe, Yoshio ; Lopatina, Olga
概要:
Oxytocin (OXT) in the hypothalamus is the biological basis of social recognition, trust, and bonding. We showed that CD3
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8, a leukaemia cell marker, plays an important role in the hypothalamus in the process of OXT release in adult mice. Disruption of Cd38 (Cd38-/-) produced impairment of maternal behavior and male social recognition in mice, similar to the behavior observed in Oxt and OXT receptor (Oxtr) gene knockout (Oxt-/- and Oxtr-/-, respectively) mice. Locomotor activity induced by separation from the dam was higher and the number of ultrasonic vocalization (USV) calls was lower in Cd38-/- than Cd38+/+ pups. These phenotypes seemed to be caused by the high plasma OXT levels during development from neonates to 3-week-old juvenile mice. ADP-ribosyl cyclase activity was markedly lower in the knockout mice from birth, suggesting that weaning for mice is a critical time window of differentiating plasma OXT. Contribution by breastfeeding was an important exogenous source for regulating plasma OXT before weaning by the presence of OXT in milk and the dam's mammary glands. The dissimilarity of Cd38-/- infant behaviour to Oxt-/- or Oxtr-/- mice can be explained partly by this exogenous source of OXT. These results suggest that secretion of OXT into the brain in a CD38-dependent manner may play an important role in the development of social behavior, and mice with OXT signalling deficiency, including Cd38-/-, Oxt -/- and Oxtr-/- mice are good animal models for developmental disorders, such as autism. © 2011 Pharmaceutical Society of Japan.
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| 5.
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Munesue, Toshio ; Yokoyama, Shigeru ; Nakamura, Kazuhiko ; Anitha, Ayyappan ; Yamada, Kazuo ; Hayashi, Kenshi ; Asaka, Tomoya ; Liu, Hong-Xiang ; Jin, Duo ; Koizumi, Keita ; Islam, Mohammad Saharul ; Huang, Jian-Jun ; Ma, Wen-Jie ; Kim, Uh-Hyun ; Kim, Sun-Jun ; Park, Keunwan ; Kim, Dongsup ; Kikuchi, Mitsuru ; Ono, Yasuki ; Nakatani, Hideo ; Suda, Shiro ; Miyachi, Taishi ; Hirai, Hirokazu ; Salmina, Alla ; Pichugina, Yu A. ; Soumarokov, Andrei A. ; Takei, Nori ; Mori, Norio ; Tsujii, Masatsugu ; Sugiyama, Toshiro ; Yagi, Kunimasa ; Yamagishi, Masakazu ; Sasaki, Tsukasa ; Yamasue, Hidenori ; Kato, Nobumasa ; Hashimoto, Ryota ; Taniike, Masako ; Hayashi, Yutaka ; Hamada, Jun-ichiro ; Suzuki, Shioto ; Ooi, Akishi ; Noda, Mami ; Kamiyama, Yuko ; Kido, Mizuho A. ; Lopatina, Olga ; Hashii, Minako ; Amina, Sarwat ; Malavasi, Fabio ; Huang, Eric J. ; Zhang, Jiasheng ; Shimizu, Nobuaki ; Yoshikawa, Takeo ; Matsushima, Akihiro ; Minabe, Yoshio ; Higashida, Haruhiro
概要:
金沢大学医薬保健研究域医学系<br />The neurobiological basis of autism spectrum disorder (ASD) remains poorly understood. Given the rol
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e of CD38 in social recognition through oxytocin (OT) release, we hypothesized that CD38 may play a role in the etiology of ASD. Here, we first examined the immunohistochemical expression of CD38 in the hypothalamus of post-mortem brains of non-ASD subjects and found that CD38 was colocalized with OT in secretory neurons. In studies of the association between CD38 and autism, we analyzed 10 single nucleotide polymorphisms (SNPs) and mutations of CD38 by re-sequencing DNAs mainly from a case-control study in Japan, and Caucasian cases mainly recruited to the Autism Genetic Resource Exchange (AGRE). The SNPs of CD38, rs6449197 (p< 0.040) and rs3796863 (p< 0.005) showed significant associations with a subset of ASD (IQ > 70; designated as high-functioning autism (HFA)) in the U.S. 104 AGRE family trios, but not with Japanese 188 HFA subjects. A mutation that caused tryptophan to replace arginine at amino acid residue 140 (R140W; (rs1800561, 4693C>T)) was found in 0.6-4.6% of the Japanese population and was associated with ASD in the smaller case-control study. The SNP was clustered in pedigrees in which the fathers and brothers of T-allele-carrier probands had ASD or ASD traits. In this cohort OT plasma levels were lower in subjects with the T allele than in those without. One proband with the T allele who was taking nasal OT spray showed relief of symptoms. The two variant CD38 poloymorphysms tested may be of interest with regard of the pathophysiology of ASD. © 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society.
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| 6.
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Lopatina, Olga ; Yoshihara, Toru ; Nishimura, Tomoko ; Zhong, Jing ; Akther, Shirin ; Fakhrul, Azam A.K.M. ; Liang, Mingkun ; Higashida, Chiharu ; Sumi, Kohei ; Furuhara, Kazumi ; Inahata, Yuki ; Huang, Jina-Jung ; Koizumi, Keita ; Yokoyama, Shigeru ; Tsuji, Takahiro ; Petugina, Yulia ; Sumarokov, Andrei ; Salmina, Alla B. ; Hashida, Koji ; Kitao, Yasuko ; Hori, Osamu ; Asano, Masahide ; Kitamura, Yoji ; Kozaka, Takashi ; Shiba, Kazuhiro ; Zhong, Fangfang ; Xie, Min-Jue ; Sato, Makoto ; Ishihara, Katsuhiro ; Higashida, Haruhiro ; 吉原, 亨 ; 小泉, 恵太 ; 横山, 茂 ; 北尾, 康子 ; 堀, 修 ; 浅野, 雅秀 ; 北村, 暘二 ; 小阪, 孝史 ; 柴, 和弘
概要:
金沢大学疾患モデル総合研究センター<br />CD157, known as bone marrow stromal cell antigen-1, is a glycosylphosphatidylinositolanchored ADP
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-ribosyl cyclase that supports the survival and function of B-lymphocytes and hematopoietic or intestinal stem cells. Although CD157/Bst1 is a risk locus in Parkinson's disease (PD), little is known about the function of CD157 in the nervous system and contribution to PD progression. Here, we show that no apparent motor dysfunction was observed in young knockout (CD157-/-) male mice under less aging-related effects on behaviors. CD157-/- mice exhibited anxiety-related and depression-like behaviors compared with wild-type mice. These behaviors were rescued through treatment with anti-psychiatric drugs and oxytocin. CD157 was weakly expressed in the amygdala and c-Fos immunoreactivity in the amygdala was less evident in CD157-/- mice than in wild-type mice. These results demonstrate for the first time that CD157 plays a role as a neuro-regulator and suggest a potential role in pre-motor symptoms in PD. © 2014 Lopatina, Yoshihara, Nishimura, Zhong, Akther, Fakhrul, Liang, Higashida, Sumi, Furuhara, Inahata, Huang, Koizumi, Yokoyama, Tsuji, Petugina, Sumarokov, Salmina, Hashida, Kitao, Hori, Asano, Kitamura, Kozaka, Shiba, Zhong, Xie, Sato, Ishihara and Higashida.<br />CC-BY 4.0
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