※一部利用できない機能があります
| 1.
論文 |
論文
|
棟居, 俊夫 ; Munesue, Toshio
概要:
金沢大学子どものこころの発達研究センター<br />Oxytocin is a neuropeptide that is released into the general circulation from the nerve ending
…
s of the posterior pituitary and into the brain from dendrites. The half-life of oxytocin in the brain is longer than that in the blood (about 20 min vs. 2 min, respectively) . Oxytocin is involved in social recognition, pair bonding, and maternal behavior. The transmembrane glycoprotein CD38 regulates oxytocin release, and CD38-knockout mice show insufficient oxytocin release. We have found a single nucleotide polymorphism (SNP) in the exon region of the CD38 gene in a subpopulation of individuals with autism spectrum disorder (ASD) . Oxytocin signaling, including CD38 and oxytocin receptor, is suggested to play an important role in the pathophysiology of ASD, although we did not demonstrate an association between the CD38 gene SNP and ASD. Oxytocin administered using a nasal spray penetrates directly into the brain and not via the general circulation. Four studies have suggested the effectiveness of a single shot of oxytocin in the treatment of ASD. We observed marked improvement in severe irritability shown by two ASD patients using oxytocin nasal spray. The effectiveness of oxytocin in the long-term treatment of patients with ASD should be rigorously investigated in a randomized controlled crossover trial.<br />Oxytocin は下垂体後葉から血中に分泌されるだけでなく，主に樹状突起から脳内にも分泌される。この際に CD38 が重要な役割を担っており，CD38 knockout マウスでは oxytocin の十分な分泌がなされない。CD38 の DNA 解析により，exon 部分のある single nucleotide polymorphism（SNP）を有する自閉症スペクトラム障害（autism spectrum disorder ： ASD）者の血中 oxytocin 濃度は SNPを有さない ASD 者に比べ有意に低かったが，この SNP と ASD との関連性を十分に示すことはできなかった。鼻腔投与された oxytocin は血液循環を経ずに直接に脳内に移行すると考えられる。また脳内では半減期が長く，広く拡散することが可能であり，かつ受容体に結合するとその神経細胞は oxy-tocin をさらに分泌する。Oxytocin が ASD の症状の一部を改善する臨床研究がいくつかある。 Oxytocin nasal spray による ASD 者を対象とした長期間の臨床試験が望まれる。
続きを見る
|
||||
| 2.
論文 |
論文
|
Higashida, Haruhiro ; Kamimura, Shin-ya ; Inoue, Takeshi ; Hori, Osamu ; Islam, Mohammad Saharul ; Lopatina, Olga ; Tsuji, Chiharu ; 東田, 陽博 ; 堀, 修 ; 辻, 知陽
概要:
The role of cyclic ADP-ribose (cADPR) as a second messenger and modulator of the mTOR pathway downstream of dopamine (DA
…
) receptors and/or CD38 was re-examined in the mouse. ADP-ribosyl activity was low in the membranes of neonates, but DA stimulated it via both D1- and D2-like receptors. ADP-ribosyl cyclase activity increased significantly during development in association with increased expression of CD38. The cADPR binding proteins, FKBP12 and FKBP12.6, were expressed in the adult mouse striatum. The ratio of phosphorylated to non-phosphorylated S6 kinase (S6K) in whole mouse striatum homogenates decreased after incubation of adult mouse striatum with extracellular cADPR for 5 min. This effect of cADPR was much weaker in MPTP-treated Parkinson’s disease model mice. The inhibitory effects of cADPR and rapamycin were identical. These data suggest that cADPR is an endogenous inhibitor of the mTOR signaling pathway downstream of DA receptors in the mouse striatum and that cADPR plays a certain role in the brain in psychiatric and neurodegenerative diseases. © 2016 Springer-Verlag Wien<br />Embargo Period 12 months
続きを見る
|
||||
| 3.
論文 |
論文
|
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
…
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.
続きを見る
|
||||
| 4.
論文 |
論文
|
東田, 陽博 ; 劉, 鴻翔 ; ロパティナ, オルガ
|
||||
| 5.
論文 |
論文
|
Higashida, Haruhiro
概要:
子どものこころの発達研究センター<br />Oxytocin (OT) is released into the brain from the cell soma, axons, and dendrites of neurosecretor
…
y cells in the hypothalamus. Locally released OT can activate OT receptors, form inositol-1,4,5-trisphosphate and elevate intracellular free calcium (Ca2+) concentrations [(Ca2+)i] in self and neighboring neurons in the hypothalamus, resulting in further OT release: i.e., autocrine or paracrine systems of OT-induced OT release. CD38-dependent cyclic ADP-ribose (cADPR) is also involved in this autoregulation by elevating [Ca2+]i via Ca2+ mobilization through ryanodine receptors on intracellular Ca2+ pools that are sensitive to both Ca2+ and cADPR. In addition, it has recently been reported that heat stimulation and hyperthermia enhance [Ca2+]i increases by Ca2+ influx, probably through TRPM2 cation channels, suggesting that cADPR and TRPM2 molecules act as Ca2+ signal amplifiers. Thus, OT release is not simply due to depolarization–secretion coupling. Both of these molecules play critical roles not only during labor and milk ejection in reproductive females, but also during social behavior in daily life in both genders. This was clearly demonstrated in CD38 knockout mice in that social behavior was impaired by reduction of [Ca2+]i elevation and subsequent OT secretion. Evidence for the associations of CD38 with social behavior and psychiatric disorder is discussed, especially in subjects with autism spectrum disorder. © 2015 The Author(s)<br />Embargo Period 12 months
続きを見る
|
||||
| 6.
論文 |
論文
|
東田, 陽博
概要:
オキシトシンは脳内に放出され、扁桃体をはじめとする「社会脳」領域を介して社会性行動、特に信頼を基礎とするあらゆる人間相互間活動に影響を与える。オキシトシン遺伝子や受容体、オキシトシンの脳内分泌を制御するCD38などがそれらの機能を司る。オキ
…
シトシンの鼻腔単回投与により健常人、自閉症スペクトラム障害者ともに、目を見るなどの対人関係行動の改善や促進があり、連続投与により、社会性障害症状の改善が報告されている。オキシトシンの末梢投与により、オキシトシンは脳脊髄液中や脳内へ移行すると思われるが、まだ十分な証拠はなく、移行の分子メカニズムを含めて、今後の研究が待たれる。 We have previously demonstrated that CD38, a transmembrane protein with ADP-ribosyl cyclase activity, plays a critical role 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. The etiology of ASDs remains largely unknown and pharmacological treatments are needed. Therefore, we investigated single nucleotide polymorphisms(SNPs) in the human CD38 gene in ASD subjects. We found several SNPs in this gene. The SNP rs3796863 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, leads to the substitution of an arginine(R) at codon 140 by tryptophan(W; R140W) in CD38. This mutation was found in 4 probands of ASD and in family members of 3 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. Our preliminary study reveals that one proband with the R140W allele or 3 other ASD patients out of 6 receiving intranasal OXT for 0.5-3 years showed improvement in areas of social approach, eye contact and communication behaviors, emotion, irritability, and aggression. 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. Further studies are necessary how intranasal OXT gets into the brain bypassing the blood-brain barrier.
続きを見る
|
||||
| 7.
論文 |
論文
|
Salmina, Alla B. ; Lopatina, Olga ; Kuvacheva, Natalia V. ; Higashida, Haruhiro
概要:
This review summarizes the literature and our own data regarding the role of NAD+-glycohydrolase/CD38- controlled molecu
…
lar mechanisms of hypothalamic and pituitary oxytocin secretion in social behavior regulation. Current approaches to the modulation of both CD38 expression and brain cell activity that represent prospective treatments for disorders associated with altered social behavior are discussed. © 2013 Bentham Science Publishers.
続きを見る
|
||||
| 8.
論文 |
論文
|
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
…
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.
続きを見る
|
||||
| 9.
論文 |
論文
|
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
…
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.
続きを見る
|
||||
| 10.
論文 |
論文
|
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
…
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.
続きを見る
|
