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| 1.
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その他
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横山, 茂 ; Yokoyama, Shigeru
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| 2.
論文 |
論文
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Higashida, Haruhiro ; Salmina, Alla ; Hashii, Minako ; Yokoyama, Shigeru ; Zhang, Jia-Sheng ; Noda, Mami ; Zhong, Zen-Guo
概要:
金沢大学大学院医学系研究科脳細胞分子学<br />ADP-ribosyl cyclase activity in the crude membrane fraction of neuroblastoma × glioma NGPM1-27
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hybrid cells was measured by monitoring [3H] cyclic ADP-ribose (cADPR) formation from [3H] NAD+. Bradykinin (BK) at 100 nM increased ADP-ribosyl cyclase activity by about 2.5-fold. Application of 300 nM BK to living NGPM1-27 cells decreased NAD+ to 78% of the prestimulation level at 30 s. In contrast, intracellular cADPR concentrations were increased by 2-3-fold during the period from 30 to 120 s after the same treatment. Our results suggest that cADPR is one of the second messengers downstream of B2 BK receptors. © 2006 Federation of European Biochemical Societies.
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| 3.
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論文
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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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| 4.
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論文
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Higashida, Haruhiro ; Liang, Mingkun ; Yoshihara, Toru ; Akther, Shirin ; Fakhrul, Azam ; Stanislav, Cherepanov ; Nam, Tae-Sik ; Kim, Uh-Hyun ; Kasai, Satoka ; Nishimura, Tomoko ; Al Mahmuda, Naila ; Yokoyama, Shigeru ; Ishihara, Katsuhiko ; Gerasimenko, Maria ; Salmina, Alla ; Zhong, Jing ; Tsuji, Takahiro ; Tsuji, Chiharu ; Lopatina, Olga
概要:
Background: Recent rodent and human studies provide evidence in support of the fact that CD157, well known as bone marro
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w stromal cell antigen-1 (BST-1) and a risk factor in Parkinson's disease, also meaningfully acts in the brain as a neuroregulator and affects social behaviors. It has been shown that social behaviors are impaired in CD157 knockout mice without severe motor dysfunction and that CD157/BST1 gene single nucleotide polymorphisms are associated with autism spectrum disorder in humans. However, it is still necessary to determine how this molecule contributes to the brain's physiological and pathophysiological functions. Methods: To gain fresh insights about the relationship between the presence of CD157 in the brain and its enzymatic activity, and aberrant social behavior, CD157 knockout mice of various ages were tested. Results: CD157 immunoreactivity colocalized with nestin-positive cells and elements in the ventricular zones in E17 embryos. Brain CD157 mRNA levels were high in neonates but low in adults. Weak but distinct immunoreactivity was detected in several areas in the adult brain, including the amygdala. CD157 has little or no base exchange activity, but some ADP-ribosyl cyclase activity, indicating that CD157 formed cyclic ADP-ribose but much less nicotinic acid adenine dinucleotide phosphate, with both mobilizing Ca2+ from intracellular Ca2+ pools. Social avoidance in CD157 knockout mice was rescued by a single intraperitoneal injection of oxytocin. Conclusions: CD157 may play a role in the embryonic and adult nervous systems. The functional features of CD157 can be explained in part through the production of cyclic ADP-ribose rather than nicotinic acid adenine dinucleotide phosphate. Further experiments are required to elucidate how the embryonic expression of CD157 in neural stem cells contributes to behaviors in adults or to psychiatric symptoms. © 2017 The Author(s).
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| 5.
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論文
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Higashida, Haruhiro ; Yokoyama, Shigeru ; Tsuji, Chiharu ; Muramatsu, Shin-ichi
概要:
We overview the 16-kDa proteolipid mediatophore, the transmembrane c-subunit of the V0 sector of the vacuolar proton ATP
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ase (ATP6V0C) that was shown to mediate the secretion of acetylcholine. Acetylcholine, serotonin, and dopamine (DA) are released from cell soma and/or dendrites if ATP6V0C is expressed in cultured cells. Adeno-associated viral vector-mediated gene transfer of ATP6V0C into the caudate putamen enhanced the depolarization-induced overflow of endogenous DA in Parkinson-model mice. Motor impairment was ameliorated in hemiparkinsonian model mice when ATP6V0C was expressed with DA-synthesizing enzymes. The review discusses application in the future as a potential tool for gene therapy, cell transplantation therapy, and inducible pluripotent stem cell therapy in neurological diseases, from the view point of recent findings regarding vacuolar ATPase. © 2016, The Physiological Society of Japan and Springer Japan.
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| 6.
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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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| 7.
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論文
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Al Mahmuda, Naila ; Yokoyama, Shigeru ; Huang, Jian-Jun ; Liu, Li ; Munesue, Toshio ; Nakatani, Hideo ; Hayashi, Kenshi ; Yagi, Kunimasa ; Yamagishi, Masakazu ; Higashida, Haruhiro
概要:
Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with complex genetic etiology. Recent studies
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have indicated that children with ASD may have altered folate or methionine metabolism, suggesting that the folate-methionine cycle may play a key role in the etiology of ASD. SLC19A1, also referred to as reduced folate carrier 1 (RFC1), is a member of the solute carrier group of transporters and is one of the key enzymes in the folate metabolism pathway. Findings from multiple genomic screens suggest the presence of an autism susceptibility locus on chromosome 21q22.3, which includes SLC19A1. Therefore, we performed a case-control study in a Japanese population. In this study, DNA samples obtained from 147 ASD patients at the Kanazawa University Hospital in Japan and 150 unrelated healthy Japanese volunteers were examined by the sequence-specific primer-polymerase chain reaction method pooled with fluorescence correlation spectroscopy. p < 0.05 was considered to represent a statistically significant outcome. Of 13 single nucleotide polymorphisms (SNPs) examined, a significant p-value was obtained for AA genotype of one SNP (rs1023159, OR = 0.39, 95% CI = 0.16-0.91, p = 0.0394; Fisher’s exact test). Despite some conflicting results, our findings supported a role for the polymorphism rs1023159 of the SLC19A1 gene, alone or in combination, as a risk factor for ASD. However, the findings were not consistent after multiple testing corrections. In conclusion, although our results supported a role of the SLC19A1 gene in the etiology of ASD, it was not a significant risk factor for the ASD samples analyzed in this study. © 2016 by the authors; licensee MDPI, Basel, Switzerland.
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| 8.
図書 |
図書
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Yokoyama, Shigeru
概要:
Inflammatory cytokines play important roles in a variety of pathophysiological changes associated with traumatic injury
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and demyelinating disorders in the peripheral nervous system. After sciatic nerve injury, proinflammatory cytokines such as interleukin 1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) are produced by and act on neurons, Schwann cells, and infiltrating inflammatory cells at the lesion site. Underlying these processes is receptor-mediated activation of intracellular signaling pathways that regulate cell differentiation and proliferation and synthesis of axon and myelin components. This review focuses on roles of inflammatory cytokines in the degeneration and regeneration of the peripheral nerve. In addition, we describe here altered expression of inflammatory cytokines in gradually elongated rat sciatic nerves. This experimental model, which is devoid of Wallerian degeneration, provides insights into the involvement of inflammatory cytokines in the maintenance of myelinated axons. Based on the findings obtained from nerve elongation models and those from conventional nerve injury models, we discuss the molecular mechanism that ensures the integrity of the peripheral nerve. © 2011 by Nova Science Publishers, Inc. All rights reserved.
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| 9.
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論文
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Duo, Jin ; Muramatsu, Shin-ichi ; Shimizu, Nobuaki ; Yokoyama, Shigeru ; Hirai, Hirokazu ; Yamada, Kiyofumi ; Liu, Hong-Xiang ; Higashida, Chiharu ; Hashii, Minako ; Higashida, Akihiko ; Asano, Masahide ; Ohkuma, Shoji ; Higashida, Haruhiro
概要:
A 16-kDa proteolipid, mediatophore, in Torpedo electric organs mediates Ca 2+-dependent acetylcholine release. Mediatoph
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ore is identical to the pore-forming stalk c-subunit of the V0 sector of vacuolar proton ATPase (ATP6V0C). The function of ATP6V0C in the mammalian central nervous system is not clear. Here, we report transfection of adeno-associated viral vectors harboring rat ATP6V0C into the mouse substantia nigra, in which high potassium stimulation increased overflow of endogenous dopamine (DA) measured in the striatum by in vivo microdialysis. Next, in the striatum of 6-hydroxydopamine- lesioned mice, a model of Parkinson's disease (PD), human tyrosine hydroxylase, aromatic l-amino-acid decarboxylase and guanosine triphosphate cyclohydrolase 1, together with or without ATP6V0C, were expressed in the caudoputamen for rescue. Motor performance on the accelerating rotarod test and amphetamine-induced ipsilateral rotation were improved in the rescued mice coexpressing ATP6V0C. [ 3H]DA, taken up into cultured N18 neuronal tumor cells transformed to express ATP6V0C, was released by potassium stimulation. These results indicated that ATP6V0C mediates DA release from nerve terminals in the striatum of DA neurons of normal mice and from gene-transferred striatal cells of parkinsonian mice. The results suggested that ATP6V0C may be useful as a rescue molecule in addition to DA-synthetic enzymes in the gene therapy of PD. © 2011 Elsevier Ltd. All rights reserved.
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| 10.
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論文
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Higashida, Haruhiro ; Yokoyama, Shigeru ; Huang, Jian-Jun ; Liu, Li ; Ma, Wen-Jie ; Akther, Shirin ; Higashida, Chiharu ; Kikuchi, Mitsuru ; Minabe, Yoshio ; Munesue, Toshio
概要:
Previously, we demonstrated that CD38, a transmembrane protein with ADP-ribosyl cyclase activity, plays a critical role
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in mouse social behavior by regulating the release of oxytocin (OXT), which is essential for mutual recognition. When CD38 was disrupted, social amnesia was observed in Cd38 knockout mice. The autism spectrum disorders (ASDs), characterized by defects in reciprocal social interaction and communication, occur either sporadically or in a familial pattern. However, the etiology of ASDs remains largely unknown. Therefore, the theoretical basis for pharmacological treatments has not been established. Hence, there is a rationale for investigating single nucleotide polymorphisms (SNPs) in the human CD38 gene in ASD subjects. We found several SNPs in this gene. The SNP rs3796863 (C > A) was associated with high-functioning autism (HFA) in American samples from the Autism Gene Resource Exchange. Although this finding was partially confirmed in low-functioning autism subjects in Israel, it has not been replicated in Japanese HFA subjects. The second SNP of interest, rs1800561 (4693C > T), leads to the substitution of an arginine (R) at codon 140 by tryptophan (W; R140W) in CD38. This mutation was found in four probands of ASD and in family members of three pedigrees with variable levels of ASD or ASD traits. The plasma levels of OXT in ASD subjects with the R140W allele were lower than those in ASD subjects lacking this allele. The OXT levels were unchanged in healthy subjects with or without this mutation. One proband with the R140W allele receiving intranasal OXT for approximately 3 years showed improvement in areas of social approach, eye contact and communication behaviors, emotion, irritability, and aggression. Five other ASD subjects with mental deficits received nasal OXT for various periods; three subjects showed improved symptoms, while two showed little or no effect. These results suggest that SNPs in CD38 may be possible risk factors for ASD by abrogating OXT function and that some ASD subjects can be treated with OXT in preliminary clinical trials. © 2011 Elsevier Ltd. All rights reserved.
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| 11.
論文 |
論文
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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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| 12.
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論文
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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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| 13.
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論文
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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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| 14.
論文 |
論文
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Kobayashi, Shota ; Yokoyama, Shigeru ; Maruta, Takahiro ; Negami, Masako ; Muroyama, Akiko ; Mitsumoto, Yasuhide ; Iwasa, Kazuo ; Yamada, Masahito ; Yoshikawa, Hiroaki
概要:
Autoantibody against nicotinic acetylcholine receptor (nAChR) α3 subunit has been implicated in the pathogenesis of para
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neoplastic neurological syndrome. To examine the effect of anti-α3 subunit autoantibody on cell-surface nAChRs, we established human embryonic kidney 293 cells stably co-expressing α3 and β4 subunits. Upon incubation with seropositive patient's serum, this cell line showed co-accumulation of patient's IgG and α3 subunits in the cytoplasm. These data support the hypothesis that anti-α3 subunit autoantibody induces internalization of cell-surface nAChRs and thereby impairs synaptic transmission. © 2012 Elsevier B.V. All rights reserved.
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| 15.
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論文
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Ito, Takaaki ; Ikeda, Kazuo ; Tomita, Katsuro ; Yokoyama, Shigeru
概要:
金沢大学医薬保健研究域医学系<br />The interleukin-6 (IL-6) family of cytokines is thought to be involved in the development and regene
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ration of peripheral nerves; however, their roles in myelination remain unclear. In this study, we examined the effects of IL-6 on the expression of genes for compact myelin proteins using Schwann cell cultures prepared by multiple explantation of adult rat sciatic nerves. In semi-quantitative reverse transcription-polymerase chain reaction analysis, stimulation of Schwann cells with IL-6 significantly increased the mRNA level of peripheral myelin protein 22 (PMP22), but not those of myelin protein zero and myelin basic protein. The increase in PMP22 mRNA was markedly suppressed by AG490, a Janus kinase 2 (JAK2) inhibitor, but not significantly by PD098059, a mitogen-activated protein kinase inhibitor. Immunocytochemical staining revealed that IL-6 enhanced immunoreactivities for the phosphorylated forms of both JAK2 and signal transducer and activator of transcription 3 (STAT3), as well as that for PMP22. These results indicate that IL-6 can enhance PMP22 production in Schwann cells via a JAK2-dependent pathway by probably activating STAT3 and thus may contribute to myelination. © 2010 Elsevier Ireland Ltd. All rights reserved.
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| 16.
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論文
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Department of Immunobiology ; Takahashi, Morinobu ; Sakai, Shunnosuke ; Nonaka, Masaru ; Amano, Shigetoyo ; Lai, Jing Erh ; Huang, Zhu Mig ; Miyagishi, Michiko ; Nakano, Yoriko ; Asahi, Toshiaki ; Nakayama, Kohzo ; Yu, Dae Yeul ; Yokoyama, Shigeru ; Sa-nga, Pattanakitsakul
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| 17.
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論文
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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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| 18.
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論文
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横山, 茂 ; Yokoyama, Shigeru
概要:
金沢大学子どものこころの発達研究センター<br />神経伝達物質受容体、イオンチャネルに代表される疎水性膜タンパクは、自己免疫性精神神経疾患の標的抗原となることが知られている。その診断検出システムを開発するために血自己抗原膜タンパクを大腸菌
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に大量発現させた。今回、グルタミン酸受容体サブユニット2種 (GluN1-1, GRIA2)と神経型アセチルコリン受容体サブユニット (nAChR-alpha7)の大腸菌大量発現を達成した。ナノファイバーに組み込むための溶媒の検討を行い、ファイバー化に適した条件を模索している。<br />In autoimmune neuropsychiatric diseases, neurotransmitter receptors and ionic channels are known to be targeted by autoantibodies that destruct neural tissues. In an attempt to establish a detection systems for autoantibodies, we produced these proteins in Escherichia coli. Of several proteins tried, two subunits for the glutamate receptor, GluN1-1 and GRIA2, and a neuronal nicotinic acetylcholine receptor, nAchR-alpha7 were successfully produced in large amount. We are now trying to find out media to dissolve these recombinant proteins and optimal conditions to integrate them into nanofibers.<br />研究課題/領域番号:15K15190, 研究期間(年度):2015-04-01 - 2018-03-31
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| 19.
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論文
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横山, 茂 ; Yokoyama, Shigeru
概要:
金沢大学子どものこころの発達研究センター<br />ラットの坐骨神経切断部および脊髄損傷受傷部位において、糖タンパクGpnmb（glycoproteinnon-metastatic melanomab）の発現上昇が認められた。免疫組織染色を
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行ったところ、損傷部位近傍のGpnmb免疫反応陽性細胞の少なくとも一部は、ED1、OX6、あるいはOX42陽性であった。Gpnmbはマクロファージあるいはミクログリアで産生され、末梢および中枢神経系の損傷に伴う病態変化に関与することが示唆された。<br />The expression of glycoprotein non-metastatic melanoma B (Gpnmb) was up-regulated in both sciatic nerve and spinal cord injuries. In the lesioned sites, Gpnmb-immunoreactive cells were co-stained with markers including OX-42, ED1, and OX6. These results suggest that Gpnmb, which is produced by macrophages and microglia, may play important roles in pathophysiological processes in both peripheral and central nerve injuries.<br />研究課題/領域番号:24590724, 研究期間(年度):2012-04-01 – 2015-03-31
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| 20.
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横山, 茂 ; Yokoyama, Shigeru
概要:
ラット坐骨神経切断時に細胞外に放出されることが推測される分子を探索し、その候補として糖タンパクnmb(Glycoprotein non-metastatic melanoma B : Gpnmb)を同定した。Gpnmbは坐骨神経切断端に浸潤
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するマクロファージに検出された。さらに、正常ラットの脊髄後角I、II層のミクログリア細胞にも存在した。これらの結果から、Gpnmbは痛み情報伝達の調節に関与することが示唆された。<br />We explored genes whose protein products were assumed to be released into the extracellular space after axotomy of rat sciatic nerve, and identified glycoprotein non-metastatic melanoma B(Gpnmb) as a candidate. Gpnmb expression was detected in infiltrating macrophages in the nerve ends. Also, Gpnmb was expressed in microglia in the layers I and II of the spinal dorsal horn of normal rats. These results suggest that Gpnmb might be involved in the modulation of pain transduction.<br />研究課題/領域番号:21600002, 研究期間(年度):2009-2011
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| 21.
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横山, 茂 ; Yokoyama, Shigeru
概要:
抗カリウムチャネル(Kv1.1、Kv1.2)抗体を作製し、末梢神経系での局在を調べた。その結果、これらのチャネルはk筋および皮膚に分布する非侵害性感覚受容ニューロンに優位に発現していた。また、神経損傷後にKv1.2チャネルの発現低下が見られ
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た。これらの結果から、Kv1.2チャネルの神経損傷時の発現低下が、非痛覚(触覚、振動覚、温度覚等)ニューロンと二次痛覚ニューロンとの異所性シナプスの形成と相侯って、痛覚過敏、アロディニアで観察されるような過剰膜興奮を来たす可能性が示唆された。末梢神経の損傷および損傷前段階で誘導される因子を同定するために、成体ラットの坐骨神経を延長した。伸長速度が1.0、2.0、20.0mm/日の3群に分け、いずれも合計20.0mmまで伸長した。腰部脊髄後根神経節および坐骨神経からRNAを抽出し、インターロイキン1β(IL1β)、インターロイキン6(IL6)、腫瘍壊死因子α(TNFα)、神経成長因子(NGF)、脳由来神経栄養因子(BDNF)、ニューロトロフィン3(NT-3)、ニューロトロフィン4/5(NT-4/5)のmRNAの発現量をRT-PCRによって調べた。腰部脊髄後根神経節では、IL6のmRNA量が顕著に上昇し、TNFα、NGF、BDNF、NT-3、NT-4/5のmRNA量に変化は認められなかった。また、坐骨神経では、TNFαのmRNA量が上昇し、IL1β、IL6、NGF、BDNF、NT-3、NT-4/5のmRNA量に変化は認められなかった。これらの発現上昇は、Waller変性が認められない1.0、2.0mm/日群でも有意であった。IL6、TNFαは、神経損傷時にニューロン、シュワン細胞で誘導される主要な因子であると想定された。今後、IL6およびTNFαが膜電位依存性チャネル(特にKv1.1とKv1.2)の発現量を変化させるかどうか調べる予定である。<br />Kvl.1 and Kv1.2 are closely related pore-forming subunits of voltage-gated potassium (K+) channels, and are abundantly expressed in the peripheral nervous system. To clarify biological roles of these subunits in primary sensory afferentiation, we performed immunohistochemical analysis using specific polyclonal antidodies. In immunopeoxidase staining, dorsal root and trigeminal ganglia revealed that intense immunoreactivity (IR) for Kvl.1 and Kv1.2 was prediominant in medium to large cell bodies of primary sensory neurons. Double-immunofluorescence experiments revealed that the strongly immunoreactive neurons were most frequently RT97 (neurofilament)-positive; but rarely peripherin-or IB4-positive. In the spinad dorsal horn, both the anti-Kvl.1 and anti-Kv1.2 antibodies heavily stained the deeper laminae III-IV. These results suggest that voltage-gated channels composed of Kvl.1 and/or Kv1.2 subunits may play important roles in conducting mechanoceptive and proprioceptive sensation from skin and muscles. We also observed that, when sciatic nerve was ligated, Kv1.2-IR was reduced in DRG neurons. We now hypothesize that activities of particular subtypes of K+ channels are reduced after peripheral nerve injury, resulting in abnormal excitability of primary sensory neurons, (manuscript, in preparation) In pararell, we attempted to identify proteins unregulated after peripheral nerve perturbation. We demonstrated that sciatic nerve elongation induces production of interleukin-6 (IL-6) in DRG neurons and tumor necrosis factor-alpha (TNF-α) in Schwann cells. The induction was detected not only in the acutely elongated 20-mm/d group, in which nuclear eccentricity in the cell body and degenerated axons were observed, but also in the gradually elongated 1-and 2-mm/d groups, in which no degenerative change was detectable. These data indicate that the expression levels of IL-6 and TNF-α are regulated delicately in the peripheral nervous system. (Osamura, et al., Exp. Neurol. 191: 61-70, 2005; Hagiwara et al., J. Orthop. Sci.10: 614-621, 2005) In the future, we will examine whether or not IL-6 and TNF-α alter expression levels of Kvl.1 and Kv1.2 proteins in neuropathic pain models.<br />研究課題/領域番号:15500255, 研究期間(年度):2003-2005<br />出典：「一次求心性Aβ線維のイオンチャネル発現異常が神経障害性疼痛発生に与える影響」研究成果報告書 課題番号15500255 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
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| 22.
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横山, 茂 ; Yokoyama, Shigeru
概要:
研究経過・結果は以下の通りである。1.ラット膜電位依存性カリウムチャネルの構成サブユニット(Kv1.1とKv1.2)のアミノ酸配列にもとずく合成ペプチドをウサギに免疫し、抗血清を抗原ペプチド結合カラムクロマトグラフィーによって精製した。2.
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上記抗体を用いてKv1.1あるいはKv1.2の相補DNAを導入したCOS-7細胞で特異的な免疫染色が認められた。いずれの抗体でも、ラット小脳膜分画を用いたウエスタンブロット解析において、特異的なバンドを検出された。3.ラット腰部脊髄後根神経節と三叉神経節を酵素抗体法によって染色したところ、Kv1.1あるいはKv1.2の免疫反応性は中型から大型の神経細胞体で観察された。これらの細胞体の50%以上はニューロフィラメント(RT97)陽性であった。ペリフェリンと同時陽性の細胞は僅かであった。4.脊髄後角では、Kv1.1、Kv1.2の免疫反応性は深部III-IV層で顕著であった。5.ヒラメ筋では、Kv1.1およびKv1.2の免疫反応性が螺旋状の構造物に認められ、抗ニューロフィラメント抗体にも反応性を示したことから感覚ニューロンの末梢側受容体であることが示唆された。6.下肢皮下への蛍光標識金コロイド注入後に標識されるL4後根神経節内の細胞体の一部はKv1.1あるいはKv1.2陽性であり、皮膚感覚ニューロンの少なくとも一部にこれらのチャネルが発現していることが示された。7.坐骨神経切断後の腰部脊髄後根神経節でKv1.1およびKv1.2の免疫反応性の低下が認められた。したがって、生理的状態でKv.1.1、Kv1.2チャネルは筋および皮膚に分布する非侵害性感覚受容ニューロンにおける活動電位の大きさ、頻度、伝播等を調節していると示唆された。同時に、これらのチャネルの発現低下は神経損傷後の痛覚過敏、アロディニアの一因となる可能性が推測された。<br />Kv1.1 and Kv1.2, two most closely related members of the Shaker-like gene subfamily, encode pore-forming subuaits of voltage-gated potassium (K^+) channels. To clarify physiological roles of these proteins in primary sensory afferentiation, we have performed inimunohistochemical analysis using specific antidodies. Immunoperoxidase staining of dorsal root and trigeminal ganglia revealed that strong immunoreactivity (IR) for Kv1.1 and Kv1.2 was predominant in medium- and large-sized neurons. In double-immunofluorescence experiments, the cells strongly positive for these subunits were most frequently observed in RT97 (neurofilament)-positive large neurons; but rarely in peripherin- or IB4-positive small neurons. In the spinal dorsal horn, both the aati-Kv1.1 and anti-Kv1.2 antibodies heavily staiaed the deeper laminae III-IV. At the electron microscopic level, IRs for these proteins were preferentially localized in myelinated axons with large diameter. These results suggest that voltage-gated K^+ channels composed of Kv 1.1 and/or Kv 1.2 subunits may play important roles in conducting mechanoceptive and proprioceptiye sensation from skin and muscles. Conceivably, decreased expression of these channels after injury might cause hypereexcitability of neurons, thereby leading to hyperalgegia or allodyaia.<br />研究課題/領域番号:11680753, 研究期間(年度):1999-2002<br />出典：「電位依存性ナトリウム・カリウムチャネルの神経障害性疼痛に伴う発現異常の分子機構」研究成果報告書 課題番号11680753 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
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| 23.
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横山, 茂 ; Yokoyama, Shigeru
概要:
金沢大学医薬保健研究域医学系<br />1. カリウム(K+)チャネル(Kv3.la)のアミノ(N)末端、カルボキシ(C)末端、および第1膜貫通領域と第2膜貫通領域を連結する細胞外ループの3か所のアミノ酸配列にもとずく合成ペプチドに対する抗
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体を作製した。これに加えて、Kv1.2チャネルのアミノ(N)末端に対する抗体も作製した。2. Kv3.1aのalternative splicing variantであるKv3.1bをマウス小脳からクローン化した。Kv3.1bはC末端細胞内領域のみKv3.1aと異なる。3. Kv3.1bをGFP(Green fluorescent protein)標識し、Kv3.laと同時に培養神経細胞株に発現させた。Kv3.1aを認識する抗体、およびKv3.1bに付加したGFPを異なる蛍光波長で検出したところ両者の細胞内分布に差異がみられた。Kv3.1aはより微細な神経突起にまで広く分布するのに対して、Kv3.1bの局在は細胞体近傍に限られる傾向があった。4. 以上より、Kv3.1aおよびKv3.1bのチャネル蛋白は異なるアンカー(anchor)蛋白に会合している可能性が示唆される。今後Kv3.1aおよびKv3.1bのC末端領域を餌(bait)にしてtwo-hybridシステムのcDNAライブラリーをスクリーニングする予定である。5. 上記1の抗Kv1.2抗体を用いてラット感覚神経節の免疫染色を行ったところ、中型から大型の細胞体に強い染色が観察された。Kv1.2チャネルは触覚等の特定の感覚の伝達に大きく関与することが示唆された。<br />研究課題/領域番号:09780720, 研究期間(年度):1997 – 1998<br />出典：「膜電位依存性K^+チャネル(KV3.1)に会合する調節蛋白のcDNAクローニング」研究成果報告書 課題番号09780720（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-9780720/)を加工して作成
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横山, 茂 ; Yokoyama, Shigeru
概要:
金沢大学医薬保健研究域医学系<br />末梢神経損傷後の慢性疼痛には、感覚ニューロンの過剰興奮と共に交感神経終末の異常な発芽(sprouting)を伴うことが多い。本研究では、これらの変化を誘導する分子を同定するための実験をおこなった。慢性
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成体ラットの左坐骨神経を切断し、3-7日後に近位側断端および健常側の右坐骨神経幹からmRNAを抽出した。cDNAを合成した後、サブトラクション・ハイブリダイゼーション法を行い、cDNAクローン約150個を得た。これらの塩基配列を決定し、GenBank/EMBL/DDBJに登録されているデータと比較したところ、89%が既存の配列と一致もしくは高い相同性を示した。コードされるタンパクは、細胞外マトリックスおよび細胞膜表面分子、細胞骨格関連分子、リン酸化酵素等の代謝酵素、分泌タンパク、RNA合成関連分子、タンパク合成関連分子、細胞周期・DNA複製関連分子、その他に分類された。これらの中から、分泌性タンパクの構造を備えているホルモン等のタンパクと細胞外マトリックスタンパクについて検討した。ポリスチレンのプレートをVI型コラーゲンで被覆すると、神経成長因子で刺激したラッ褐色細胞種由来PC12細胞の突起伸展が誘導されるのに対し、非被覆時には誘導されなかった。(Yokoyama S, et. al. Soc. Neurosci. Abstr. 872.21,2007)これらの観察から、VI型コラーゲンには、疼痛発生時の神経回路の可塑的変化に関与する可能性が示唆された。膜電位依存性Na^+チャネルの発現増加あるいはK^+チャネルの発現低下をもたらす活性の有無について調べる予定である。また今回単離した他のcDNAクローンについても、交感神経終末の発芽誘導活性とイオンチャネルの発現誘導(あるいは抑制)活性の両面から検討する予定である。<br />Altered ionic channel expression and sympathetic nerve sprouting have been thought to underlie a condition of chronic pain, such as complex regional pain syndrome. Following a few weeks after injury, postganglionic sympathetic nerve endings sprout and surround cell bodies of dorsal root ganglion (DRG) neurons, and make abnormal synaptic contacts. Aberrant interactions between sensory and sympathetic neurons are also located in the peripheral sites including neuroma at a transected nerve and intradermal region. Despite extensive studies, however, little is known about the molecules that promote the outgrowth of sympathetic nerve. To identify chronic pain-associated proteins, we screened a subtractive cDNA library enriched for mRNAs increased in the proximal stump of transected rat sciatic nerve. Among the identified proteins, collagen type VI was induced prominently in the proximal stump. Collagen type VI-coated plastic plate allowed robust neurite outgrowth of dorsal root and superior cervical ganglion neurons dissociated from adult rats, NSC34 spinal motor neuron-like cells, and PC12 pheochromocytoma cells. The neurite-promoting effect was more long-lasting than those in collagen type I-, laminin-, poly-D-ornithine-, and poly-L-lysine-coated plates. In addition, coating with collagen type VI prevented death of PC12 and NSC34 cells to the extent comparable to laminin. Immunohistochemical analysis of damaged sciatic nerve revealed that intense immunoreactivity for collagen type VI was localized in nonmyelinating Schwann cells, macrophages and fibroblasts, and along vessels and tyrosine hydroxylase (TM-positive nerve fibers. These results suggest that collagen type VI promotes not only regeneration of motor and somatosensory nerves, but also sprouting of sympathetic nerve. We are planning to examine whether somatosensory and /or sympathetic neurons in contact with collagen type VI alter expression levels of ionic channels.<br />研究課題/領域番号:18613003, 研究期間(年度):2006 – 2007<br />出典：「一次求心性Aβ線維のイオンチャネル発現調節機構の解明と難治性疼痛治療への応用」研究成果報告書 課題番号18613003（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-18613003/186130032007kenkyu_seika_hokoku_gaiyo/)を加工して作成
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