2024/03/29 更新

写真a

テルヌマ ミホ
照沼 美穂
TERUNUMA Miho
所属
教育研究院 医歯学系 歯学系列 教授
医歯学総合研究科 口腔生命科学専攻 顎顔面再建学 教授
職名
教授
外部リンク

学位

  • 高等教育学(Postgraduate Certificate in Academic Practice in Higher Education) ( 2016年2月   英国 レスター大学 )

  • 博士(歯学) ( 2004年3月   九州大学 )

  • 歯学士 ( 2000年3月   九州大学 )

研究分野

  • ライフサイエンス / 神経科学一般

  • ライフサイエンス / 常態系口腔科学

  • ライフサイエンス / 病態系口腔科学

経歴(researchmap)

  • 新潟大学   口腔生化学分野   教授

    2016年8月 - 現在

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  • University of Leicester, College of Medicine, Biological Sciences and Psychology   Department of Neuroscience, Psychology and Behaviour   Lecturer in Neuroscience

    2013年10月 - 2016年7月

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  • Tufts University School of Medicine   Department of Neuroscience   Research Associate

    2009年7月 - 2013年10月

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  • Tufts University School of Medicine   Department of Neuroscience   Postdoctoral Associate

    2008年7月 - 2009年6月

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  • University of Pennsylvania   Department of Neuroscience   Postdoctoral Fellow

    2005年8月 - 2008年7月

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  • 九州大学   口腔細胞工学   学術研究員

    2005年4月 - 2005年7月

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  • 九州大学   口腔細胞工学   日本学術振興会特別研究員(DC2)

    2003年4月 - 2005年3月

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▶ 全件表示

経歴

  • 新潟大学   医歯学総合研究科 口腔生命科学専攻 顎顔面再建学   教授

    2016年8月 - 現在

 

論文

  • Behavioral analysis of kainate receptor KO mice and the role of GluK3 subunit in anxiety. 国際誌

    Izumi Iida, Kohtarou Konno, Rie Natsume, Manabu Abe, Masahiko Watanabe, Kenji Sakimura, Miho Terunuma

    Scientific reports   14 ( 1 )   4521 - 4521   2024年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Kainate receptors (KARs) are one of the ionotropic glutamate receptors in the central nervous system (CNS) comprised of five subunits, GluK1-GluK5. There is a growing interest in the association between KARs and psychiatric disorders, and there have been several studies investigating the behavioral phenotypes of KAR deficient mice, however, the difference in the genetic background has been found to affect phenotype in multiple mouse models of human diseases. Here, we examined GluK1-5 single KO mice in a pure C57BL/6N background and identified that GluK3 KO mice specifically express anxiolytic-like behavior with an alteration in dopamine D2 receptor (D2R)-induced anxiety, and reduced D2R expression in the striatum. Biochemical studies in the mouse cortex confirmed that GluK3 subunits do not assemble with GluK4 and GluK5 subunits, that can be activated by lower concentration of agonists. Overall, we found that GluK3-containing KARs function to express anxiety, which may represent promising anti-anxiety medication targets.

    DOI: 10.1038/s41598-024-55063-z

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  • Behavioral analysis of kainate receptor KO mice and the role of GluK3 subunit in anxiety

    Izumi Iida, Kohtarou Konno, Rie Natsume, Manabu Abe, Masahiko Watanabe, Kenji Sakimura, Miho Terunuma

    Scientific Reports   14 ( 1 )   2024年2月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    Abstract

    Kainate receptors (KARs) are one of the ionotropic glutamate receptors in the central nervous system (CNS) comprised of five subunits, GluK1-GluK5. There is a growing interest in the association between KARs and psychiatric disorders, and there have been several studies investigating the behavioral phenotypes of KAR deficient mice, however, the difference in the genetic background has been found to affect phenotype in multiple mouse models of human diseases. Here, we examined GluK1-5 single KO mice in a pure C57BL/6N background and identified that GluK3 KO mice specifically express anxiolytic-like behavior with an alteration in dopamine D2 receptor (D2R)-induced anxiety, and reduced D2R expression in the striatum. Biochemical studies in the mouse cortex confirmed that GluK3 subunits do not assemble with GluK4 and GluK5 subunits, that can be activated by lower concentration of agonists. Overall, we found that GluK3-containing KARs function to express anxiety, which may represent promising anti-anxiety medication targets.

    DOI: 10.1038/s41598-024-55063-z

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    その他リンク: https://www.nature.com/articles/s41598-024-55063-z

  • The Role of Genetically Modified Human Feeder Cells in Maintaining the Integrity of Primary Cultured Human Deciduous Dental Pulp Cells. 国際誌

    Natsumi Ibano, Emi Inada, Shinji Otake, Yuki Kiyokawa, Kensuke Sakata, Masahiro Sato, Naoko Kubota, Hirofumi Noguchi, Yoko Iwase, Tomoya Murakami, Tadashi Sawami, Yoshito Kakihara, Takeyasu Maeda, Miho Terunuma, Yutaka Terao, Issei Saitoh

    Journal of clinical medicine   11 ( 20 )   2022年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Tissue-specific stem cells exist in tissues and organs, such as skin and bone marrow. However, their pluripotency is limited compared to embryonic stem cells. Culturing primary cells on plastic tissue culture dishes can result in the loss of multipotency, because of the inability of tissue-specific stem cells to survive in feeder-less dishes. Recent findings suggest that culturing primary cells in medium containing feeder cells, particularly genetically modified feeder cells expressing growth factors, may be beneficial for their survival and proliferation. Therefore, the aim of this study was to elucidate the role of genetically modified human feeder cells expressing growth factors in maintaining the integrity of primary cultured human deciduous dental pulp cells. Feeder cells expressing leukemia inhibitory factor, bone morphogenetic protein 4, and basic fibroblast growth factor were successfully engineered, as evidenced by PCR. Co-culturing with mitomycin-C-treated feeder cells enhanced the proliferation of newly isolated human deciduous dental pulp cells, promoted their differentiation into adipocytes and neurons, and maintained their stemness properties. Our findings suggest that genetically modified human feeder cells may be used to maintain the integrity of primary cultured human deciduous dental pulp cells.

    DOI: 10.3390/jcm11206087

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  • Ammonia induces amyloidogenesis in astrocytes by promoting amyloid precursor protein translocation into the endoplasmic reticulum. 国際誌

    Ayaka Komatsu, Izumi Iida, Yusuke Nasu, Genki Ito, Fumiko Harada, Sari Kishikawa, Stephen J Moss, Takeyasu Maeda, Miho Terunuma

    The Journal of biological chemistry   298 ( 5 )   101933 - 101933   2022年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hyperammonemia is known to cause various neurological dysfunctions such as seizures and cognitive impairment. Several studies have suggested that hyperammonemia may also be linked to the development of Alzheimer's disease (AD). However, the direct evidence for a role of ammonia in the pathophysiology of AD remains to be discovered. Herein, we report that hyperammonemia increases the amount of mature amyloid precursor protein (mAPP) in astrocytes, the largest and most prevalent type of glial cells in the central nervous system that are capable of metabolizing glutamate and ammonia, and promotes amyloid beta (Aβ) production. We demonstrate the accumulation of mAPP in astrocytes was primarily due to enhanced endocytosis of mAPP from the plasma membrane. A large proportion of internalized mAPP was targeted not to the lysosome, but to the endoplasmic reticulum, where processing enzymes β-secretase BACE1 (beta-site APP cleaving enzyme 1) and γ-secretase presenilin-1 are expressed, and mAPP is cleaved to produce Aβ. Finally, we show the ammonia-induced production of Aβ in astrocytic endoplasmic reticulum was specific to Aβ42, a principal component of senile plaques in AD patients. Our studies uncover a novel mechanism of Aβ42 production in astrocytes and also provide the first evidence that ammonia induces the pathogenesis of AD by regulating astrocyte function.

    DOI: 10.1016/j.jbc.2022.101933

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  • Perivascular Hedgehog responsive cells play a critical role in peripheral nerve regeneration via controlling angiogenesis. 国際誌

    Yurie Yamada, Jun Nihara, Supaluk Trakanant, Takehisa Kudo, Kenji Seo, Izumi Iida, Kenji Izumi, Masayuki Kurose, Yutaka Shimomura, Miho Terunuma, Takeyasu Maeda, Atsushi Ohazama

    Neuroscience research   173   62 - 70   2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hh signaling has been shown to be activated in intact and injured peripheral nerve. However, the role of Hh signaling in peripheral nerve is not fully understood. In the present study, we observed that Hh signaling responsive cells [Gli1(+) cells] in both the perineurium and endoneurium. In the endoneurium, Gli1(+) cells were classified as blood vessel associated or non-associated. After injury, Gli1(+) cells around blood vessels mainly proliferated to then accumulate into the injury site along with endothelial cells. Hh signaling activity was retained in Gli1(+) cells during nerve regeneration. To understand the role of Hedgehog signaling in Gli1(+) cells during nerve regeneration, we examined mice with Gli1(+) cells-specific inactivation of Hh signaling (Smo cKO). After injury, Smo cKO mice showed significantly reduced numbers of accumulated Gli1(+) cells along with disorganized vascularization at an early stage of nerve regeneration, which subsequently led to an abnormal extension of the axon. Thus, Hh signaling in Gli1(+) cells appears to be involved in nerve regeneration through controlling new blood vessel formation at an early stage.

    DOI: 10.1016/j.neures.2021.06.003

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  • A comparative analysis of kainate receptor GluK2 and GluK5 knockout mice in a pure genetic background 査読 国際誌

    Izumi Iida, Kohtarou Konno, Rie Natsume, Manabu Abe, Masahiko Watanabe, Kenji Sakimura, Miho Terunuma

    Behavioural Brain Research   405   113194 - 113194   2021年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier {BV}  

    Kainate receptors (KARs) are members of the glutamate receptor family that regulate synaptic function in the brain. Although they are known to be associated with psychiatric disorders, how they are involved in these disorders remains unclear. KARs are tetrameric channels assembled from a combination of GluK1-5 subunits. Among these, GluK2 and GluK5 subunits are the major heteromeric subunits in the brain. To determine the functional similarities and differences between GluK2 and GluK5 subunits, we generated GluK2 KO and GluK5 KO mice on a C57BL/6N background, a well-characterized inbred strain, and compared their behavioral phenotypes. We found that GluK2 KO and GluK5 KO mice exhibited the same phenotypes in many tests, such as reduced locomotor activity, impaired motor function, and enhanced depressive-like behavior. No change was observed in motor learning, anxiety-like behavior, or sociability. Additionally, we identified subunit-specific phenotypes, such as reduced motivation toward their environment in GluK2 KO mice and an enhancement in the contextual memory in GluK5 KO mice. These results revealed that GluK2 and GluK5 subunits not only function in a coordinated manner but also have a subunit-specific role in regulating behavior. To summarize, we demonstrated subunit-specific and common behavioral effects of GluK2 and GluK5 subunits for the first time. Moreover, to the best of our knowledge, this is the first evidence of the involvement of the GluK5 subunit in the expression of depressive-like behavior and contextual memory, which strongly indicates its role in psychiatric disorders.

    DOI: 10.1016/j.bbr.2021.113194

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  • Drug-Induced Naïve iPS Cells Exhibit Better Performance than Primed iPS Cells with Respect to the Ability to Differentiate into Pancreatic β-Cell Lineage. 査読 国際誌

    Yuki Kiyokawa, Masahiro Sato, Hirofumi Noguchi, Emi Inada, Yoko Iwase, Naoko Kubota, Tadashi Sawami, Miho Terunuma, Takeyasu Maeda, Haruaki Hayasaki, Issei Saitoh

    Journal of clinical medicine   9 ( 9 )   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Pluripotent stem cells are classified as naïve and primed cells, based on their in vitro growth characteristics and potential to differentiate into various types of cells. Human-induced pluripotent stem cells (iPSCs, also known as epiblast stem cells [EpiSCs]) have limited capacity to differentiate and are slightly more differentiated than naïve stem cells (NSCs). Although there are several in vitro protocols that allow iPSCs to differentiate into pancreatic lineage, data concerning generation of β-cells from these iPSCs are limited. Based on the pluripotentiality of NSCs, it was hypothesized that NSCs can differentiate into pancreatic β-cells when placed under an appropriate differentiation induction condition. We examined whether NSCs can be efficiently induced to form potentially pancreatic β cells after being subjected to an in vitro protocol. Several colonies resembling in vitro-produced β-cell foci, with β-cell-specific marker expression, were observed when NSC-derived embryoid bodies (EBs) were induced to differentiate into β-cell lineage. Conversely, EpiSC-derived EBs failed to form such foci in vitro. Intrapancreatic grafting of the in vitro-formed β-cell foci into nude mice (BALB/c-nu/nu) generated a cell mass containing insulin-producing cells (IPCs), without noticeable tumorigenesis. These NSCs can be used as a promising resource for curing type 1 diabetes.

    DOI: 10.3390/jcm9092838

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  • Sustained laryngeal transient receptor potential vanilloid 1 activation inhibits mechanically induced swallowing in anesthetized rats. 査読 国際誌

    Midori Yoshihara, Takanori Tsujimura, Taku Suzuki, Kouta Nagoya, Naru Shiraishi, Jin Magara, Miho Terunuma, Makoto Inoue

    American journal of physiology. Gastrointestinal and liver physiology   319 ( 3 )   G412-G419   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A major component of gastric acid is hydrochloric acid (HCl), which can activate transient receptor potential vanilloid 1 (TRPV1). In the present study, we investigated how sustained laryngeal TRPV1 activation affects the frequency of the swallowing reflex. Experiments were carried out on 85 male Sprague-Dawley rats. The effects of short and sustained application of chemicals (3 µl of 0.1 N HCl or capsaicin) on the frequency of swallowing and on time-dependent changes in the occurrence of swallowing evoked by supralaryngeal nerve stimulation were determined. To evaluate vascular permeability of the larynx, Evans blue dye was intravenously injected after 5 or 60 min of sustained TRPV1 activation. SB366791 (a TRPV1 inhibitor) and Cap/QX-314 (a TRPV1-expressed neuronal inhibitor) significantly inhibited HCl/capsaicin-induced swallowing, but air flow-induced swallowing was not affected. Although the number of air flow-induced swallows followed by capsaicin stimulation was not affected within 5 min, it was significantly reduced by 60-min capsaicin or HCl application. The swallowing threshold associated with supralaryngeal nerve stimulation did not significantly change throughout the recording period. Evans blue dye concentrations in the larynx were significantly higher at 60 min in the 10-5 M capsaicin group than in the control group. Our results suggest that sustained TPRV1 activation not only desensitizes TRPV1 but also inactivates mechanoreceptors, which may be attributed to increases in vascular permeability and edema, as part of an inflammatory process.NEW & NOTEWORTHY Although a transient receptor potential vanilloid 1 (TRPV1) inhibitor or TRPV1-expressed neuronal inhibitor significantly inhibited HCl/capsaicin-evoked swallowing, air flow-induced swallowing was not affected. The number of air flow-induced swallows was significantly reduced within 60 min of TRPV1 activation. Evans blue dye concentration in the larynx increased 60 min after capsaicin application. TPRV1 activation not only desensitizes TRPV1 but also inactivates mechanoreceptors caused by increases in vascular permeability and edema.

    DOI: 10.1152/ajpgi.00082.2020

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  • Direct Interaction of PP2A Phosphatase with GABAB Receptors Alters Functional Signaling. 査読 国際誌

    Xiaofan Li, Miho Terunuma, Tarek G Deeb, Shari Wiseman, Menelas N Pangalos, Angus C Nairn, Stephen J Moss, Paul A Slesinger

    The Journal of neuroscience : the official journal of the Society for Neuroscience   40 ( 14 )   2808 - 2816   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Addictive drugs usurp the brain's intrinsic mechanism for reward, leading to compulsive and destructive behaviors. In the ventral tegmental area (VTA), the center of the brain's reward circuit, GABAergic neurons control the excitability of dopamine (DA) projection neurons and are the site of initial psychostimulant-dependent changes in signaling. Previous work established that cocaine/methamphetamine exposure increases protein phosphatase 2A (PP2A) activity, which dephosphorylates the GABABR2 subunit, promotes internalization of the GABAB receptor (GABABR) and leads to smaller GABABR-activated G-protein-gated inwardly rectifying potassium (GIRK) currents in VTA GABA neurons. How the actions of PP2A become selective for a particular signaling pathway is poorly understood. Here, we demonstrate that PP2A can associate directly with a short peptide sequence in the C terminal domain of the GABABR1 subunit, and that GABABRs and PP2A are in close proximity in rodent neurons (mouse/rat; mixed sexes). We show that this PP2A-GABABR interaction can be regulated by intracellular Ca2+ Finally, a peptide that potentially reduces recruitment of PP2A to GABABRs and thereby limits receptor dephosphorylation increases the magnitude of baclofen-induced GIRK currents. Thus, limiting PP2A-dependent dephosphorylation of GABABRs may be a useful strategy to increase receptor signaling for treating diseases.SIGNIFICANCE STATEMENT Dysregulation of GABAB receptors (GABABRs) underlies altered neurotransmission in many neurological disorders. Protein phosphatase 2A (PP2A) is involved in dephosphorylating and subsequent internalization of GABABRs in models of addiction and depression. Here, we provide new evidence that PP2A B55 regulatory subunit interacts directly with a small region of the C-terminal domain of the GABABR1 subunit, and that this interaction is sensitive to intracellular Ca2+ We demonstrate that a short peptide corresponding to the PP2A interaction site on GABABR1 competes for PP2A binding, enhances phosphorylation GABABR2 S783, and affects functional signaling through GIRK channels. Our study highlights how targeting PP2A dependent dephosphorylation of GABABRs may provide a specific strategy to modulate GABABR signaling in disease conditions.

    DOI: 10.1523/JNEUROSCI.2654-19.2020

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  • Repeated human deciduous tooth-derived dental pulp cell reprogramming factor transfection yields multipotent intermediate cells with enhanced iPS cell formation capability. 査読 国際誌

    Miki Soda, Issei Saitoh, Tomoya Murakami, Emi Inada, Yoko Iwase, Hirofumi Noguchi, Shinji Shibasaki, Mie Kurosawa, Tadashi Sawami, Miho Terunuma, Naoko Kubota, Yutaka Terao, Hayato Ohshima, Haruaki Hayasaki, Masahiro Sato

    Scientific reports   9 ( 1 )   1490 - 1490   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Human tissue-specific stem cells (hTSCs), found throughout the body, can differentiate into several lineages under appropriate conditions in vitro and in vivo. By transfecting terminally differentiated cells with reprogramming factors, we previously produced induced TSCs from the pancreas and hepatocytes that exhibit additional properties than iPSCs, as exemplified by very low tumour formation after xenogenic transplantation. We hypothesised that hTSCs, being partially reprogrammed in a state just prior to iPSC transition, could be isolated from any terminally differentiated cell type through transient reprogramming factor overexpression. Cytochemical staining of human deciduous tooth-derived dental pulp cells (HDDPCs) and human skin-derived fibroblasts following transfection with Yamanaka's factors demonstrated increased ALP activity, a stem cell marker, three weeks after transfection albeit in a small percentage of clones. Repeated transfections (≤3) led to more efficient iPSC generation, with HDDPCs exhibiting greater multipotentiality at two weeks post-transfection than the parental intact HDDPCs. These results indicated the utility of iPSC technology to isolate TSCs from HDDPCs and fibroblasts. Generally, a step-wise loss of pluripotential phenotypes in ESCs/iPSCs occurs during their differentiation process. Our present findings suggest that the reverse phenomenon can also occur upon repeated introduction of reprogramming factors into differentiated cells such as HDDPCs and fibroblasts.

    DOI: 10.1038/s41598-018-37291-2

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  • A Role for Prefrontal Cortical NMDA Receptors in Murine Alcohol-Heightened Aggression. 査読 国際誌

    Emily L Newman, Miho Terunuma, Tiffany L Wang, Nishani Hewage, Matthew B Bicakci, Stephen J Moss, Joseph F DeBold, Klaus A Miczek

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology   43 ( 6 )   1224 - 1234   2018年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nature Publishing Group  

    Alcohol is associated with nearly half of all violent crimes committed in the United States; yet, a potential neural basis for this type of pathological aggression remains elusive. Alcohol may act on N-methyl-d-aspartate receptors (NMDARs) within cortical circuits to impede processing and to promote aggression. Here, male mice were characterized as alcohol-heightened (AHAs) or alcohol non-heightened aggressors (ANAs) during resident-intruder confrontations after self-administering 1.0 g/kg alcohol (6% w/v) or water. Alcohol produced a pathological-like pattern of aggression in AHAs; these mice shifted their bites to more vulnerable locations on the body of a submissive animal, including the anterior back and ventrum after consuming alcohol. In addition, through immunoblotting, we found that AHAs overexpressed the NMDAR GluN2D subunit in the prefrontal cortex (PFC) as compared to ANAs while the two phenotypes expressed similar levels of GluN1, GluN2A and GluN2B. After identifying several behavioral and molecular characteristics that distinguish AHAs from ANAs, we tested additional mice for their aggression following preferential antagonism of GluN2D-containing NMDARs. In these experiments, groups of AHAs and ANAs self-administered 1.0 g/kg alcohol (6% w/v) or water before receiving intraperitoneal (i.p.) doses of ketamine or memantine, or infusions of memantine directly into the prelimbic (PLmPFC) or infralimbic medial PFC (ILmPFC). Moderate doses of IP ketamine, IP memantine, or intra-PLmPFC memantine increased aggression in AHAs, but only in the absence of alcohol. Prior alcohol intake blocked the pro-aggressive effects of ketamine or memantine. In contrast, only memantine, administered systemically or intra-PLmPFC, interacted with prior alcohol intake to escalate aggression in ANAs. Intra-ILmPFC memantine had no effect on aggression in either AHAs or ANAs. In sum, this work illustrates a potential role of GluN2D-containing NMDARs in the PLmPFC in alcohol-heightened aggression. GluN2D-containing NMDARs are highly expressed on cortical parvalbumin-containing interneurons, suggesting that, in a subset of individuals, alcohol may functionally alter signal integration within cortical microcircuits to dysregulate threat reactivity and promote aggression. This work suggests that targeting GluN2D-NMDARs may be of use in reducing the impact of alcohol-related violence in the human population.

    DOI: 10.1038/npp.2017.253

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  • Diversity of structure and function of GABAB receptors: a complexity of GABAB-mediated signaling. 査読

    Miho Terunuma

    Proceedings of the Japan Academy. Series B, Physical and biological sciences   94 ( 10 )   390 - 411   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    γ-aminobutyric acid type B (GABAB) receptors are broadly expressed in the nervous system and play an important role in neuronal excitability. GABAB receptors are G protein-coupled receptors that mediate slow and prolonged inhibitory action, via activation of Gαi/o-type proteins. GABAB receptors mediate their inhibitory action through activating inwardly rectifying K+ channels, inactivating voltage-gated Ca2+ channels, and inhibiting adenylate cyclase. Functional GABAB receptors are obligate heterodimers formed by the co-assembly of R1 and R2 subunits. It is well established that GABAB receptors interact not only with G proteins and effectors but also with various proteins. This review summarizes the structure, subunit isoforms, and function of GABAB receptors, and discusses the complexity of GABAB receptors, including how receptors are localized in specific subcellular compartments, the mechanism regulating cell surface expression and mobility of the receptors, and the diversity of receptor signaling through receptor crosstalk and interacting proteins.

    DOI: 10.2183/pjab.94.026

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  • A Role for the GIRK3 Subunit in Methamphetamine-Induced Attenuation of GABAB Receptor-Activated GIRK Currents in VTA Dopamine Neurons. 査読 国際誌

    Michaelanne B Munoz, Claire L Padgett, Robert Rifkin, Miho Terunuma, Kevin Wickman, Candice Contet, Stephen J Moss, Paul A Slesinger

    The Journal of neuroscience : the official journal of the Society for Neuroscience   36 ( 11 )   3106 - 14   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOC NEUROSCIENCE  

    UNLABELLED: Repeated exposure to psychostimulants induces locomotor sensitization and leads to persistent changes in the circuitry of the mesocorticolimbic dopamine (DA) system. G-protein-gated inwardly rectifying potassium (GIRK; also known as Kir3) channels mediate a slow IPSC and control the excitability of DA neurons. Repeated 5 d exposure to psychostimulants decreases the size of the GABAB receptor (GABABR)-activated GIRK currents (IBaclofen) in ventral tegmental area (VTA) DA neurons of mice, but the mechanism underlying this plasticity is poorly understood. Here, we show that methamphetamine-dependent attenuation of GABABR-GIRK currents in VTA DA neurons required activation of both D1R-like and D2R-like receptors. The methamphetamine-dependent decrease in GABABR-GIRK currents in VTA DA neurons did not depend on a mechanism of dephosphorylation of the GABAB R2 subunit found previously for other neurons in the reward pathway. Rather, the presence of the GIRK3 subunit appeared critical for the methamphetamine-dependent decrease of GABABR-GIRK current in VTA DA neurons. Together, these results highlight different regulatory mechanisms in the learning-evoked changes that occur in the VTA with repeated exposure to psychostimulants. SIGNIFICANCE STATEMENT: Exposure to addictive drugs such as psychostimulants produces persistent adaptations in inhibitory circuits within the mesolimbic dopamine system, suggesting that addictive behaviors are encoded by changes in the reward neural circuitry. One form of neuroadaptation that occurs with repeated exposure to psychostimulants is a decrease in slow inhibition, mediated by a GABAB receptor and a potassium channel. Here, we examine the subcellular mechanism that links psychostimulant exposure with changes in slow inhibition and reveal that one type of potassium channel subunit is important for mediating the effect of repeated psychostimulant exposure. Dissecting out the components of drug-dependent plasticity and uncovering novel protein targets in the reward circuit may lead to the development of new therapeutics for treating addiction.

    DOI: 10.1523/JNEUROSCI.1327-15.2016

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  • Compromising the phosphodependent regulation of the GABAAR β3 subunit reproduces the core phenotypes of autism spectrum disorders. 査読 国際誌

    Thuy N Vien, Amit Modgil, Armen M Abramian, Rachel Jurd, Joshua Walker, Nicholas J Brandon, Miho Terunuma, Uwe Rudolph, Jamie Maguire, Paul A Davies, Stephen J Moss

    Proceedings of the National Academy of Sciences of the United States of America   112 ( 48 )   14805 - 10   2015年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATL ACAD SCIENCES  

    Alterations in the efficacy of neuronal inhibition mediated by GABAA receptors (GABAARs) containing β3 subunits are continually implicated in autism spectrum disorders (ASDs). In vitro, the plasma membrane stability of GABAARs is potentiated via phosphorylation of serine residues 408 and 409 (S408/9) in the β3 subunit, an effect that is mimicked by their mutation to alanines. To assess if modifications in β3 subunit expression contribute to ASDs, we have created a mouse in which S408/9 have been mutated to alanines (S408/9A). S408/9A homozygotes exhibited increased phasic, but decreased tonic, inhibition, events that correlated with alterations in the membrane stability and synaptic accumulation of the receptor subtypes that mediate these distinct forms of inhibition. S408/9A mice exhibited alterations in dendritic spine structure, increased repetitive behavior, and decreased social interaction, hallmarks of ASDs. ASDs are frequently comorbid with epilepsy, and consistent with this comorbidity, S408/9A mice exhibited a marked increase in sensitivity to seizures induced by the convulsant kainic acid. To assess the relevance of our studies using S408/9A mice for the pathophysiology of ASDs, we measured S408/9 phosphorylation in Fmr1 KO mice, a model of fragile X syndrome, the most common monogenetic cause of ASDs. Phosphorylation of S408/9 was selectively and significantly enhanced in Fmr1 KO mice. Collectively, our results suggest that alterations in phosphorylation and/or activity of β3-containing GABAARs may directly contribute to the pathophysiology of ASDs.

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  • Purinergic receptor activation facilitates astrocytic GABAB receptor calcium signalling. 査読 国際誌

    Miho Terunuma, Philip G Haydon, Menelas N Pangalos, Stephen J Moss

    Neuropharmacology   88   74 - 81   2015年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Gamma-aminobutyric acid B receptors (GABABRs) are heterodimeric G-protein coupled receptors, which mediate slow synaptic inhibition in the brain. Emerging evidence suggests astrocytes also express GABABRs, although their physiological significance remains unknown. To begin addressing this issue, we have used imaging and biochemical analysis to examine the role GABABRs play in regulating astrocytic Ca(2+) signalling. Using live imaging of cultured cortical astrocytes loaded with calcium indicator Fluo-4/AM, we found that astrocytic GABABRs are able to induce astrocytic calcium transients only if they are pre-activated by P2 purinoceptors (P2YRs). The GABABR-mediated calcium transients were attenuated by the removal of extracellular calcium. Furthermore, P2YRs enhance the phosphorylation of astrocytic GABABR R2 subunits on both serine 783 (S783) and serine 892 (S892), two phosphorylation sites that are well known to regulate the activity and the cell surface stability of GABABRs. Collectively these results suggest that P2YR mediated signalling is an important determinant of GABABR activity and phosphorylation in astrocytes.

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  • Glutamine synthetase stability and subcellular distribution in astrocytes are regulated by γ-aminobutyric type B receptors. 査読 国際誌

    Deborah Huyghe, Yasuko Nakamura, Miho Terunuma, Mathilde Faideau, Philip Haydon, Menelas N Pangalos, Stephen J Moss

    The Journal of biological chemistry   289 ( 42 )   28808 - 15   2014年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    Emerging evidence suggests that functional γ-aminobutyric acid B receptors (GABABRs) are expressed by astrocytes within the mammalian brain. GABABRs are heterodimeric G-protein-coupled receptors that are composed of R1/R2 subunits. To date, they have been characterized in neurons as the principal mediators of sustained inhibitory signaling; however their roles in astrocytic physiology have been ill defined. Here we reveal that the cytoplasmic tail of the GABABR2 subunit binds directly to the astrocytic protein glutamine synthetase (GS) and that this interaction determines the subcellular localization of GS. We further demonstrate that the binding of GS to GABABR2 increases the steady state expression levels of GS in heterologous cells and in mouse primary astrocyte culture. Mechanistically this increased stability of GS in the presence of GABABR2 occurs via reduced proteasomal degradation. Collectively, our results suggest a novel role for GABABRs as regulators of GS stability. Given the critical role that GS plays in the glutamine-glutamate cycle, astrocytic GABABRs may play a critical role in supporting both inhibitory and excitatory neurotransmission.

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  • Neurosteroids promote phosphorylation and membrane insertion of extrasynaptic GABAA receptors. 査読 国際誌

    Armen M Abramian, Eydith Comenencia-Ortiz, Amit Modgil, Thuy N Vien, Yasuko Nakamura, Yvonne E Moore, Jamie L Maguire, Miho Terunuma, Paul A Davies, Stephen J Moss

    Proceedings of the National Academy of Sciences of the United States of America   111 ( 19 )   7132 - 7   2014年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATL ACAD SCIENCES  

    Neurosteroids are synthesized within the brain and act as endogenous anxiolytic, anticonvulsant, hypnotic, and sedative agents, actions that are principally mediated via their ability to potentiate phasic and tonic inhibitory neurotransmission mediated by γ-aminobutyric acid type A receptors (GABAARs). Although neurosteroids are accepted allosteric modulators of GABAARs, here we reveal they exert sustained effects on GABAergic inhibition by selectively enhancing the trafficking of GABAARs that mediate tonic inhibition. We demonstrate that neurosteroids potentiate the protein kinase C-dependent phosphorylation of S443 within α4 subunits, a component of GABAAR subtypes that mediate tonic inhibition in many brain regions. This process enhances insertion of α4 subunit-containing GABAAR subtypes into the membrane, resulting in a selective and sustained elevation in the efficacy of tonic inhibition. Therefore, the ability of neurosteroids to modulate the phosphorylation and membrane insertion of α4 subunit-containing GABAARs may underlie the profound effects these endogenous signaling molecules have on neuronal excitability and behavior.

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  • Postsynaptic GABAB receptor activity regulates excitatory neuronal architecture and spatial memory. 査読 国際誌

    Miho Terunuma, Raquel Revilla-Sanchez, Isabel M Quadros, Qiudong Deng, Tarek Z Deeb, Michael Lumb, Piotr Sicinski, Philip G Haydon, Menelas N Pangalos, Stephen J Moss

    The Journal of neuroscience : the official journal of the Society for Neuroscience   34 ( 3 )   804 - 16   2014年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOC NEUROSCIENCE  

    Cognitive dysfunction is a common symptom in many neuropsychiatric disorders and directly correlates with poor patient outcomes. The majority of prolonged inhibitory signaling in the brain is mediated via GABAB receptors (GABABRs), but the molecular function of these receptors in cognition is ill defined. To explore the significance of GABABRs in neuronal activity and cognition, we created mice with enhanced postsynaptic GABABR signaling by mutating the serine 783 in receptor R2 subunit (S783A), which decreased GABABR degradation. Enhanced GABABR activity reduced the expression of immediate-early gene-encoded protein Arc/Arg3.1, effectors that are critical for long-lasting memory. Intriguingly, S783A mice exhibited increased numbers of excitatory synapses and surface AMPA receptors, effects that are consistent with decreased Arc/Arg3.1 expression. These deficits in Arc/Arg3.1 and neuronal morphology lead to a deficit in spatial memory consolidation. Collectively our results suggest a novel and unappreciated role for GABABR activity in determining excitatory neuronal architecture and spatial memory via their ability to regulate Arc/Arg3.1.

    DOI: 10.1523/JNEUROSCI.3320-13.2013

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  • The ability of BDNF to modify neurogenesis and depressive-like behaviors is dependent upon phosphorylation of tyrosine residues 365/367 in the GABA(A)-receptor γ2 subunit. 査読 国際誌

    Vithlani M, Hines RM, Zhong P, Terunuma M, Hines DJ, Revilla-Sanchez R, Jurd R, Haydon P, Rios M, Brandon N, Yan Z, Moss SJ

    The Journal of neuroscience : the official journal of the Society for Neuroscience   33 ( 39 )   15567 - 77   2013年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1523/JNEUROSCI.1845-13.2013

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  • Enhanced tonic inhibition influences the hypnotic and amnestic actions of the intravenous anesthetics etomidate and propofol. 査読 国際誌

    Karla Kretschmannova, Rochelle M Hines, Raquel Revilla-Sanchez, Miho Terunuma, Verena Tretter, Rachel Jurd, Max B Kelz, Stephen J Moss, Paul A Davies

    The Journal of neuroscience : the official journal of the Society for Neuroscience   33 ( 17 )   7264 - 73   2013年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOC NEUROSCIENCE  

    Intravenous anesthetics exert a component of their actions via potentiating inhibitory neurotransmission mediated by γ-aminobutyric type-A receptors (GABAARs). Phasic and tonic inhibition is mediated by distinct populations of GABAARs, with the majority of phasic inhibition by subtypes composed of α1-3βγ2 subunits, whereas tonic inhibition is dependent on subtypes assembled from α4-6βδ subunits. To explore the contribution that these distinct forms of inhibition play in mediating intravenous anesthesia, we have used mice in which tyrosine residues 365/7 within the γ2 subunit are mutated to phenyalanines (Y365/7F). Here we demonstrate that this mutation leads to increased accumulation of the α4 subunit containing GABAARs in the thalamus and dentate gyrus of female Y365/7F but not male Y365/7F mice. Y365/7F mice exhibited a gender-specific enhancement of tonic inhibition in the dentate gyrus that was more sensitive to modulation by the anesthetic etomidate, together with a deficit in long-term potentiation. Consistent with this, female Y365/7F, but not male Y365/7F, mice exhibited a dramatic increase in the duration of etomidate- and propofol-mediated hypnosis. Moreover, the amnestic actions of etomidate were selectively potentiated in female Y365/7F mice. Collectively, these observations suggest that potentiation of tonic inhibition mediated by α4 subunit containing GABAARs contributes to the hypnotic and amnestic actions of the intravenous anesthetics, etomidate and propofol.

    DOI: 10.1523/JNEUROSCI.5475-12.2013

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  • Methamphetamine-evoked depression of GABA(B) receptor signaling in GABA neurons of the VTA. 査読 国際誌

    Claire L Padgett, Arnaud L Lalive, Kelly R Tan, Miho Terunuma, Michaelanne B Munoz, Menelas N Pangalos, José Martínez-Hernández, Masahiko Watanabe, Stephen J Moss, Rafael Luján, Christian Lüscher, Paul A Slesinger

    Neuron   73 ( 5 )   978 - 89   2012年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CELL PRESS  

    Psychostimulants induce neuroadaptations in excitatory and fast inhibitory transmission in the ventral tegmental area (VTA). Mechanisms underlying drug-evoked synaptic plasticity of slow inhibitory transmission mediated by GABA(B) receptors and G protein-gated inwardly rectifying potassium (GIRK/Kir(3)) channels, however, are poorly understood. Here, we show that 1 day after methamphetamine (METH) or cocaine exposure both synaptically evoked and baclofen-activated GABA(B)R-GIRK currents were significantly depressed in VTA GABA neurons and remained depressed for 7 days. Presynaptic inhibition mediated by GABA(B)Rs on GABA terminals was also weakened. Quantitative immunoelectron microscopy revealed internalization of GABA(B1) and GIRK2, which occurred coincident with dephosphorylation of serine 783 (S783) in GABA(B2), a site implicated in regulating GABA(B)R surface expression. Inhibition of protein phosphatases recovered GABA(B)R-GIRK currents in VTA GABA neurons of METH-injected mice. This psychostimulant-evoked impairment in GABA(B)R signaling removes an intrinsic brake on GABA neuron spiking, which may augment GABA transmission in the mesocorticolimbic system.

    DOI: 10.1016/j.neuron.2011.12.031

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  • Cyclin E constrains Cdk5 activity to regulate synaptic plasticity and memory formation. 査読 国際誌

    Junko Odajima, Zachary P Wills, Yasmine M Ndassa, Miho Terunuma, Karla Kretschmannova, Tarek Z Deeb, Yan Geng, Sylwia Gawrzak, Isabel M Quadros, Jennifer Newman, Manjusri Das, Marie E Jecrois, Qunyan Yu, Na Li, Frederic Bienvenu, Stephen J Moss, Michael E Greenberg, Jarrod A Marto, Piotr Sicinski

    Developmental cell   21 ( 4 )   655 - 68   2011年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CELL PRESS  

    Cyclin E is a component of the core cell cycle machinery, and it drives cell proliferation by regulating entry and progression of cells through the DNA synthesis phase. Cyclin E expression is normally restricted to proliferating cells. However, high levels of cyclin E are expressed in the adult brain. The function of cyclin E in quiescent, postmitotic nervous system remains unknown. Here we use a combination of in vivo quantitative proteomics and analyses of cyclin E knockout mice to demonstrate that in terminally differentiated neurons cyclin E forms complexes with Cdk5 and controls synapse function by restraining Cdk5 activity. Ablation of cyclin E led to a decreased number of synapses, reduced number and volume of dendritic spines, and resulted in impaired synaptic plasticity and memory formation in cyclin E-deficient animals. These results reveal a cell cycle-independent role for a core cell cycle protein, cyclin E, in synapse function and memory.

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  • Astrocytic activation of A1 receptors regulates the surface expression of NMDA receptors through a Src kinase dependent pathway. 査読 国際誌

    Qiudong Deng, Miho Terunuma, Tommaso Fellin, Stephen J Moss, Philip G Haydon

    Glia   59 ( 7 )   1084 - 93   2011年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Chemical transmitters released from astrocytes, termed gliotransmitters, modulate synaptic transmission and neuronal function. Using astrocyte-specific inducible transgenicmice (dnSNARE mice), we have demonstrated that inhibiting gliotransmission leads to reduced activation of adenosine A1 receptors (A1R) and impaired sleep homeostasis (Halassa et al. (2009) Neuron 61:213-219); Pascual et al. (2005) Science 310:113-116). Additionally, synaptic N-methyl-D-aspartate receptor (NMDAR) currents are reduced in these astrocyte-specific transgenic animals (Fellin et al. (2009) Proc Natl Acad Sci USA 106:15037-15042). Because of the importance of adenosine and NMDA receptors to sleep processes we asked whether there is a causal linkage between changes in A1R activation and synaptic NMDA receptors. We show that astrocytic dnSNARE expression leads to reduced tyrosine phosphorylation of Srckinase and NR2 subunits concomitant with the decreased surface expression of the NR2 subunits. To test the role of A1R signaling in mediating these actions, we show that incubation of wildtype (WT) slices with an A1R antagonist reduces tyrosine phosphorylation of Src kinase and NR2B, decreases the surface expression of the NR2B subunits and leads to smaller NMDA component of miniature EPSCs. In dnSNARE mice we could rescue WT phenotype by incubation in an A1R agonist:activation of A1 receptor led to increased tyrosine phosphorylation of Src kinase and NR2B subunits as well as increased the surface expression of the NR2B subunit and increased NMDA component of the synaptic mEPSC. These results provide the first demonstration that astrocytes can affect neuronal excitability on a long time scale by regulating the surface expression of NMDA receptors through the activation of specific intracellular signaling pathways.

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  • The dynamic modulation of GABA(A) receptor trafficking and its role in regulating the plasticity of inhibitory synapses. 査読 国際誌

    Mansi Vithlani, Miho Terunuma, Stephen J Moss

    Physiological reviews   91 ( 3 )   1009 - 22   2011年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER PHYSIOLOGICAL SOC  

    Inhibition in the adult mammalian central nervous system (CNS) is mediated by γ-aminobutyric acid (GABA). The fast inhibitory actions of GABA are mediated by GABA type A receptors (GABA(A)Rs); they mediate both phasic and tonic inhibition in the brain and are the principle sites of action for anticonvulsant, anxiolytic, and sedative-hypnotic agents that include benzodiazepines, barbiturates, neurosteroids, and some general anesthetics. GABA(A)Rs are heteropentameric ligand-gated ion channels that are found concentrated at inhibitory postsynaptic sites where they mediate phasic inhibition and at extrasynaptic sites where they mediate tonic inhibition. The efficacy of inhibition and thus neuronal excitability is critically dependent on the accumulation of specific GABA(A)R subtypes at inhibitory synapses. Here we evaluate how neurons control the number of GABA(A)Rs on the neuronal plasma membrane together with their selective stabilization at synaptic sites. We then go on to examine the impact that these processes have on the strength of synaptic inhibition and behavior.

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  • Prolonged activation of NMDA receptors promotes dephosphorylation and alters postendocytic sorting of GABAB receptors. 査読 国際誌

    Miho Terunuma, Karina J Vargas, Megan E Wilkins, Omar A Ramírez, Matías Jaureguiberry-Bravo, Menelas N Pangalos, Trevor G Smart, Stephen J Moss, Andrés Couve

    Proceedings of the National Academy of Sciences of the United States of America   107 ( 31 )   13918 - 23   2010年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATL ACAD SCIENCES  

    Slow and persistent synaptic inhibition is mediated by metabotropic GABAB receptors (GABABRs). GABABRs are responsible for the modulation of neurotransmitter release from presynaptic terminals and for hyperpolarization at postsynaptic sites. Postsynaptic GABABRs are predominantly found on dendritic spines, adjacent to excitatory synapses, but the control of their plasma membrane availability is still controversial. Here, we explore the role of glutamate receptor activation in regulating the function and surface availability of GABABRs in central neurons. We demonstrate that prolonged activation of NMDA receptors (NMDA-Rs) leads to endocytosis, a diversion from a recycling route, and subsequent lysosomal degradation of GABABRs. These sorting events are paralleled by a reduction in GABABR-dependent activation of inwardly rectifying K+ channel currents. Postendocytic sorting is critically dependent on phosphorylation of serine 783 (S783) within the GABABR2 subunit, an established substrate of AMP-dependent protein kinase (AMPK). NMDA-R activation leads to a rapid increase in phosphorylation of S783, followed by a slower dephosphorylation, which results from the activity of AMPK and protein phosphatase 2A, respectively. Agonist activation of GABABRs counters the effects of NMDA. Thus, NMDA-R activation alters the phosphorylation state of S783 and acts as a molecular switch to decrease the abundance of GABABRs at the neuronal plasma membrane. Such a mechanism may be of significance during synaptic plasticity or pathological conditions, such as ischemia or epilepsy, which lead to prolonged activation of glutamate receptors.

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  • Functional modulation of GABAB receptors by protein kinases and receptor trafficking. 査読 国際誌

    Miho Terunuma, Menelas N Pangalos, Stephen J Moss

    Advances in pharmacology (San Diego, Calif.)   58   113 - 22   2010年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    GABA(B) receptors (GABA(B)R) are heterodimeric G protein-coupled receptors (GPCRs) that mediate slow and prolonged inhibitory signals in the central nervous system. The signaling of GPCRs is under stringent control and is subject to regulation by multiple posttranslational mechanisms. The beta-adrenergic receptor is a prototypic GPCR. Like most GPCRs, prolonged exposure of this receptor to agonist induces phosphorylation of multiple intracellular residues that is largely dependent upon the activity of G protein-coupled receptor kinases (GRKs). Phosphorylation terminates receptor-effector coupling and promotes both interaction with beta-arrestins and removal from the plasma membrane via clathrin-dependent endocytosis. Emerging evidence for GABA(B)Rs suggests that these GPCRs do not conform to this mode of regulation. Studies using both native and recombinant receptor preparations have demonstrated that GABA(B)Rs do not undergo agonist-induced internalization and are not GRK substrates. Moreover, whilst GABA(B)Rs undergo clathrin-dependent constitutive endocytosis, it is generally accepted that their rates of internalization are not modified by prolonged agonist exposure. Biochemical studies have revealed that GABA(B)Rs are phosphorylated on multiple residues within the cytoplasmic domains of both the R1 and R2 subunits by cAMP-dependent protein kinase and 5'AMP-dependent protein kinase (AMPK). Here we discuss the role that this phosphorylation plays in determining GABA(B)R effector coupling and their trafficking within the endocytic pathway and go on to evaluate the significance of GABA(B)R phosphorylation in controlling neuronal excitability under normal and pathological conditions.

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  • Direct Interaction of GABA(B) Receptors with M-2 Muscarinic Receptors Enhances Muscarinic Signaling 査読

    Stephanie B. Boyer, Sinead M. Clancy, Miho Terunuma, Raquel Revilla-Sanchez, Steven M. Thomas, Stephen J. Moss, Paul A. Slesinger

    JOURNAL OF NEUROSCIENCE   29 ( 50 )   15796 - 15809   2009年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOC NEUROSCIENCE  

    Downregulation of G-protein-coupled receptors (GPCRs) provides an important mechanism for reducing neurotransmitter signaling during sustained stimulation. Chronic stimulation of M-2 muscarinic receptors (M(2)Rs) causes internalization of M2R and G-protein-activated inwardly rectifying potassium (GIRK) channels in neuronal PC12 cells, resulting in loss of function. Here, we show that coexpression of GABA(B) R2 receptors (GBR2s) rescues both surface expression and function of M2R, including M2R-induced activation of GIRKs and inhibition of cAMP production. GBR2 showed significant association with M2R at the plasma membrane but not other GPCRs (M1R, mu-opioid receptor), as detected by fluorescence resonance energy transfer measured with total internal reflection fluorescence microscopy. Unique regions of the proximal C-terminal domains of GBR2 and M2R mediate specific binding between M2R and GBR2. In the brain, GBR2, but not GBR1, biochemically coprecipitates with M2R and overlaps with M2R expression in cortical neurons. This novel heteromeric association between M2R and GBR2 provides a possible mechanism for altering muscarinic signaling in the brain and represents a previously unrecognized role for GBR2.

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  • Deficits in spatial memory correlate with modified gamma-aminobutyric acid type A receptor tyrosine phosphorylation in the hippocampus 査読

    Verena Tretter, Raquel Revilla-Sanchez, Catriona Houston, Miho Terunuma, Robbert Havekes, Cedrick Florian, Rachel Jurd, Mansi Vithlani, Guido Michels, Andres Couve, Werner Sieghart, Nicholas Brandon, Ted Abel, Trevor G. Smart, Stephen J. Moss

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   106 ( 47 )   20039 - 20044   2009年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATL ACAD SCIENCES  

    Fast synaptic inhibition in the brain is largely mediated by gamma-aminobutyric acid receptors (GABA(A)R). While the pharmacological manipulation of GABA(A)R function by therapeutic agents, such as benzodiazepines can have profound effects on neuronal excitation and behavior, the endogenous mechanisms neurons use to regulate the efficacy of synaptic inhibition and their impact on behavior remains poorly understood. To address this issue, we created a knock-in mouse in which tyrosine phosphorylation of the GABA(A)Rs gamma 2 subunit, a posttranslational modification that is critical for their functional modulation, has been ablated. These animals exhibited enhanced GABA(A)R accumulation at postsynaptic inhibitory synaptic specializations on pyramidal neurons within the CA3 subdomain of the hippocampus, primarily due to aberrant trafficking within the endocytic pathway. This enhanced inhibition correlated with a specific deficit in spatial object recognition, a behavioral paradigm dependent upon CA3. Thus, phospho-dependent regulation of GABA(A)R function involving just two tyrosine residues in the gamma 2 subunit provides an input-specific mechanism that not only regulates the efficacy of synaptic inhibition, but has behavioral consequences.

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  • Endogenous nonneuronal modulators of synaptic transmission control cortical slow oscillations in vivo 査読

    Tommaso Fellin, Michael M. Halassa, Miho Terunuma, Francesca Succol, Hajime Takano, Marcos Frank, Stephen J. Moss, Philip G. Haydon

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   106 ( 35 )   15037 - 15042   2009年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATL ACAD SCIENCES  

    Gliotransmission, the release of molecules from astrocytes, regulates neuronal excitability and synaptic transmission in situ. Whether this process affects neuronal network activity in vivo is not known. Using a combination of astrocyte-specific molecular genetics, with in vivo electrophysiology and pharmacology, we determined that gliotransmission modulates cortical slow oscillations, a rhythm characterizing nonrapid eye movement sleep. Inhibition of gliotransmission by the expression of a dominant negative SNARE domain in astrocytes affected cortical slow oscillations, reducing the duration of neuronal depolarizations and causing prolonged hyperpolarizations. These network effects result from the astrocytic modulation of intracortical synaptic transmission at two sites: a hypofunction of postsynaptic NMDA receptors, and by reducing extracellular adenosine, a loss of tonic A1 receptor-mediated inhibition. These results demonstrate that rhythmic brain activity is generated by the coordinated action of the neuronal and glial networks.

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  • The Availability of Surface GABA(B) Receptors Is Independent of gamma-Aminobutyric Acid but Controlled by Glutamate in Central Neurons 査読

    Karina J. Vargas, Miho Terunuma, Judith A. Tello, Menelas N. Pangalos, Stephen J. Moss, Andres Couve

    JOURNAL OF BIOLOGICAL CHEMISTRY   283 ( 36 )   24641 - 24648   2008年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    The efficacy of synaptic transmission depends on the availability of ionotropic and metabotropic neurotransmitter receptors at the plasma membrane, but the contribution of the endocytic and recycling pathways in the regulation of gamma-aminobutyric acid type B (GABA(B)) receptors remains controversial. To understand the mechanisms that regulate the abundance of GABA(B) receptors, we have studied their turnover combining surface biotin labeling and a microscopic immunoendocytosis assay in hippocampal and cortical neurons. We report that internalization of GABA(B) receptors is agonist-independent. We also demonstrate that receptors endocytose in the cell body and dendrites but not in axons. Additionally, we show that GABA(B) receptors endocytose as heterodimers via clathrin- and dynamin-1-dependent mechanisms and that they recycle to the plasma membrane after endocytosis. More importantly, we show that glutamate decreases the levels of cell surface receptors in a manner dependent on an intact proteasome pathway. These observations indicate that glutamate and not GABA controls the abundance of surface GABA(B) receptors in central neurons, consistent with their enrichment at glutamatergic synapses.

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  • Deficits in phosphorylation of GABA(A) receptors by intimately associated protein kinase C activity underlie compromised synaptic inhibition during status epilepticus 査読

    Miho Terunuma, Jianwei Xu, Mansi Vithlani, Werner Sieghart, Josef Kittler, Menelas Pangalos, Philip G. Haydon, Douglas A. Coulter, Stephen J. Moss

    JOURNAL OF NEUROSCIENCE   28 ( 2 )   376 - 384   2008年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOC NEUROSCIENCE  

    Status epilepticus ( SE) is a progressive and often lethal human disorder characterized by continuous or rapidly repeating seizures. Of major significance in the pathology of SE are deficits in the functional expression of GABA(A) receptors (GABA(A)Rs), the major sites of fast synaptic inhibition in the brain. We demonstrate that SE selectively decreases the phosphorylation of GABAARs on serine residues 408/9 (S408/9) in the beta 3 subunit by intimately associated protein kinase C isoforms. Dephosphorylation of S408/9 unmasks a basic patch-binding motif for the clathrin adaptor AP2, enhancing the endocytosis of selected GABA(A)R subtypes from the plasma membrane during SE. In agreement with this, enhancing S408/9 phosphorylation or selectively blocking the binding of the beta 3 subunit to AP2 increased GABA(A)R cell surface expression levels and restored the efficacy of synaptic inhibition in SE. Thus, enhancing phosphorylation of GABA(A)Rs or selectively blocking their interaction with AP2 may provide novel therapeutic strategies to ameliorate SE.

    DOI: 10.1523/JNEUROSCI.4346-07.2008

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  • Disrupted dentate granule cell chloride regulation enhances synaptic excitability during development of temporal lobe epilepsy 査読

    Hemal R. Pathak, Florian Weissinger, Miho Terunuma, Gregory C. Carlson, Fu-Chun Hsu, Stephen J. Moss, Douglas A. Coulter

    JOURNAL OF NEUROSCIENCE   27 ( 51 )   14012 - 14022   2007年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOC NEUROSCIENCE  

    GABA(A) receptor-mediated inhibition depends on the maintenance of intracellular Cl- concentration ([Cl-](in)) at low levels. In neurons in the developing CNS, [Cl-](in) is elevated, E-GABA is depolarizing, and GABA consequently is excitatory. Depolarizing GABAergic synaptic responses may be recapitulated in various neuropathological conditions, including epilepsy. In the present study, rat hippocampal dentate granule cells were recorded using gramicidin perforated patch techniques at varying times (1-60 d) after an epileptogenic injury, pilocarpine-induced status epilepticus (STEP). In normal, non-epileptic animals, these strongly inhibited dentate granule cells act as a gate, regulating hippocampal excitation, controlling seizure initiation and/or propagation. For 2 weeks after STEP, we found that E-GABA was positively shifted in granule cells. This shift in E-GABA altered synaptic integration, increased granule cell excitability, and resulted in compromised "gate" function of the dentate gyrus. E-GABA recovered to control values at longer latencies post-STEP (2-8 weeks), when animals had developed epilepsy. During this period of shifted E-GABA, expression of the Cl- extruding K-/Cl- cotransporter, KCC2 was decreased. Application of the KCC2 blocker, furosemide, to control neurons mimicked E-GABA shifts evident in granule cells post-STEP. Furthermore, post-STEP and furosemide effects interacted occlusively, both on E-GABA in granule cells, and on gatekeeper function of the dentate gyrus. This suggests a shared mechanism, reduced KCC2 function. These findings demonstrate that decreased expression of KCC2 persists for weeks after an epileptogenic injury, reducing inhibitory efficacy and enhancing dentate granule cell excitability. This pathophysiological process may constitute a significant mechanism linking injury to the subsequent development of epilepsy.

    DOI: 10.1523/JNEUROSCI.4390-07.2007

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  • mGluR5 stimulates gliotransmission in the nucleus accumbens 査読

    Marcello D'Ascenzo, Tommaso Fellin, Miho Terunuma, Raquel Revilla-Sanchez, David F. Meaney, Yves P. Auberson, Stephen J. Moss, Philip G. Haydon

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   104 ( 6 )   1995 - 2000   2007年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATL ACAD SCIENCES  

    Although metabotropic glutamate receptor 5 (mGluR5) is essential for cocaine self-administration and drug-seeking behavior, there is limited knowledge of the cellular actions of this receptor in the nucleus accumbens (NAc). Although mGIuR5 has the potential to regulate neurons directly, recent studies have shown the importance of mGIuR5 in regulating Ca2+ signaling in astrocytes and, as a consequence, the Ca2+-dependent release of excitatory transmitters from these glia. In this study, we demonstrate that activation of mGIuR5 induces Ca2+ oscillations in NAc astrocytes with the correlated appearance of NMDA receptor-dependent slow inward currents detected in medium spiny neurons (MSNs). Photolysis of caged Ca2+ loaded specifically into astrocytes evoked slow inward currents demonstrating that Ca2+ elevations in astrocytes are responsible for these excitatory events. Pharmacological evaluation of these glial-evoked NMDA currents shows that they are mediated by NR2B-containing NMDA receptors, whereas synaptic NMDA receptors rely on NR2A-containing receptors. Stimulation of glutamatergic afferents activates mGluRS-dependent astrocytic Ca2+ oscillations and gliotransmission that is sustained for minutes beyond the initial stimulus. Because gliotransmission is mediated by NMDA receptors, depolarized membrane potentials exhibited during up-states augment excitation provided by gliotransmission, which drives bursts of MSN action potentials. Because the predominant mGluR5-dependent action of glutamatergic afferents is to cause the sustained activation of astrocytes, which in turn excite MSNs through extrasynaptic NMDA receptors, our results raise the potential for gliotransmission being involved in prolonged mGluR5-dependent adaptation in the NAc.

    DOI: 10.1073/pnas.0609408104

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  • Phospho-dependent functional modulation of GABA(B) receptors by the metabolic sensor AMP-dependent protein kinase 査読

    Nobuyuki Kuramoto, Megan E. Wilkins, Benjamin P. Fairfax, Raquel Revilla-Sanchez, Miho Terunuma, Keisuke Tamaki, Mika Iemata, Noel Warren, Andres Couve, Andrew Calver, Zsolt Horvath, Katie Freeman, David Carling, Lan Huang, Cathleen Gonzales, Edward Cooper, Trevor G. Smart, Menelas N. Pangalos, Stephen J. Moss

    NEURON   53 ( 2 )   233 - 247   2007年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CELL PRESS  

    GABA(B) receptors are heterodimeric G protein-coupled receptors composed of R1 and R2 subunits that mediate slow synaptic inhibition in the brain by activating inwardly rectifying K+ channels (GIRKs) and inhibiting Ca2+, channels. We demonstrate here that GABAB receptors are intimately associated with 5'AMP-dependent protein kinase (AMPK). AMPK acts as a metabolic sensor that is potently activated by increases in 5'AMP concentration that are caused by enhanced metabolic activity, anoxia, or ischemia. AMPK binds the R1 subunit and directly phosphorylates S783 in the R2 subunit to enhance GABAB receptor activation of GIRKs. Phosphorylation of S783 is evident in many brain regions, and is increased dramatically after ischemic injury. Finally, we also reveal that S783 plays a critical role in enhancing neuronal survival after ischemia. Together our results provide evidence of a neuroprotective mechanism, which, under conditions of metabolic stress or after ischemia, increases GABAB receptor function to reduce excitotoxicity and thereby promotes neuronal survival.

    DOI: 10.1016/j.neuron.2006.12.015

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  • Identification of a Novel Signaling Molecule and Elucidation of Its Cellular Functions —Development of an Interface between Neuroscience and Oral Health Science— 査読

    Takashi Kanematsu, Akiko Mizokami, Miho Terunuma, Hiroshi Takeuchi, Masato Hirata

    Journal of Oral Biosciences   49 ( 4 )   244 - 258   2007年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The investigation of chemically synthesized inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] analogs has led to the isolation of a novel protein with a molecular size of 130 kDa, characterized as a molecule with a domain organization similar to phospholipase C (PLC)-δ1 but lacking enzymatic activity. Two isoforms of the molecule were subsequently identified, the molecule has been named PRIP (PLC-related, but catalytically inactive protein), with the two isoforms named PRIP-1 and-2. Regarding its ability to bind Ins (1,4,5)-P3 via the pleckstrin homology domain, the involvement of PRIP-1 in Ins(1,4,5)P3-mediated Ca2+ signaling was first examined. Yeast two-hybrid screening of a brain cDNA library identified GABARAP (GABAA receptor-associated protein) and PP1 (protein phosphatase 1), which led us to examine the possible neurological involvement of PRIP, particularly in GABAA receptor signaling. PRIP-1 and-2 double knock-out (DKO) mice were analyzed for GABAA receptor function with special reference to the action of benzodiazepines whose target is the γ subunit of the receptors
    sensitivity to benzodiazepine was reduced, as assessed by biochemical, electrophysiological, and behavioral analyses of DKO mice, suggesting the dysfunction of γ2 subunit-containing GABAA receptors. The mesencephalic trigeminal nucleus, which mediates perceptions from periodontal mechanoreceptors and jaw-closer muscle spindles, receives many synaptic inputs, including those from GABAA receptors, indicating that PRIP might indirectly be involved in rhythmical jaw movement. In the present article, we summarize our current research and the functional significance of PRIP. © 2007, Japanese Association for Oral Biology. All rights reserved.

    DOI: 10.2330/joralbiosci.49.244

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  • Protein phosphatase regulation by PRIP, a PLC-related catalytically inactive protein - Implications in the phospho-modulation of the GABA(A) receptor 査読

    Satoko Yanagihori, Miho Terunuma, Kiyoshi Koyano, Takashi Kanematsu, Sung Ho Ryu, Masato Hirata

    ADVANCES IN ENZYME REGULATION, VOL 46, PROCEEDINGS   46   203 - 222   2006年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    PRIP, phospholipase C related, but catalytically inactive protein was first identified as a novel inositol 1,4,5-trisphosphate binding protein. It has a number of binding partners including protein phosphatase (PP1 and 2A), GABA(A) receptor associated protein, and the beta subunits of GABAA receptors, in addition to inositol 1,4,5-trisphosphate. The identification of these molecules led us to examine the possible involvement of PRIP in the phospho-regulation of the beta subunits of GABAA receptors using hippocampal neurons prepared from PRIP-1 and 2 double knock-out (DKO) mice. Experiments were performed with special reference to the dephosphorylation processes of the beta subunits. The phosphorylation of beta 3 subunits by the activation of protein kinase A in cortical neurons of the control mice continued for up to 5min, even after washing out of the stimulus, followed by a gradual dephosphorylation. That of DKO mice gradually increased in spite of the lower phosphorylation levels induced by the stimulation. There was little difference in the amount of cellular cyclic AMP and protein kinase A activity between the control and mutant mice, indicating that phosphatases such as PP1 and MA are primarily involved in the difference. The time course of PP1 activity changes in the vicinity of the receptors in control mice corresponded to the phosphorylation of PRIP, while that of the mutant mice decreased with the period of the incubation. This is a good agreement with the suggestion that PRIP binds to and inactivates PP1, which is regulated by the phosphorylation of PRIP at threonine 94. These results suggest that PRIP plays an important role in controlling the dynamics of GABA(A) receptor phosphorylation by through PP1 binding and, therefore, the efficacy of synaptic inhibition mediated by these receptors. (c) 2006 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.advenzreg.2006.01.006

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  • PRIP, a novel Ins(1,4,5)P-3 binding protein, functional significance in Ca2+ signaling and extension to neuroscience and beyond 査読

    T Kanematsu, H Takeuchi, M Terunuma, M Hirata

    MOLECULES AND CELLS   20 ( 3 )   305 - 314   2005年12月

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    記述言語:英語   出版者・発行元:SPRINGER SINGAPORE PTE LTD  

    Investigation of chemically synthesized inositol 1,4,5-trisphosphate [Ins(1,4,5)P-3] analogs has led to the isolation of a novel binding protein with a molecular size of 130 kDa, characterized as a molecule with similar domain organization to phospholipase C-delta 1 (PLC-delta 1) but lacking the enzymatic activity. An isoform of the molecule was subsequently identified, and these molecules have been named PRIP (PLC-related, but catalytically inactive protein), with the two isoforms named PRIP-1 and -2. Regarding its ability to bind Ins(1,4,5)P-3 via the pleckstrin homology domain, the involvement of PRIP-1 in Ins(1,4,5)P-3-mediated Ca2+ signaling was examined using COS-1 cells overexpressing PRIP-1 and cultured neurons prepared from PRIP-1 knockout mice. Yeast two hybrid screening of a brain cDNA library using a unique N-terminus as bait identified GABARAP (GABA(A) receptor associated protein) and PP1 (protein phosphatase 1), which led us to examine the possible involvement of PRIP in GABA(A) receptor signaling. For this purpose PRIP knock-out mice were analyzed for GABA(A) receptor function in relation to the action of benzodiazepines from the electrophysiological and behavioral aspects. During the course of these experiments we found that PRIP also binds to the beta-subunit of GABA(A) receptors and PP2A (protein phosphtase 2A). Here, we summarize how PRIP is involved in Ins(1,4,5)P-3-mediated Ca2+ signaling and GABA(A) receptor signaling based on the characteristics of binding molecules.

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  • Direct interaction of N-ethylmaleimide-sensitive factor with GABA(A) receptor beta subunits 査読

    H Goto, M Terunuma, T Kanematsua, Y Misumi, SJ Moss, M Hirata

    MOLECULAR AND CELLULAR NEUROSCIENCE   30 ( 2 )   197 - 206   2005年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    GABA, receptors mediate most of the fast inhibitory neurotransmission in the brain, and are believed to be composed mainly of alpha, beta, and gamma subunits. It has been shown that GABA(A) receptors interact with a number of binding partners that act to regulate both receptor function and cell surface stability. Here, we reveal that GABA(A) receptors interact directly with N-ethylmaleimide-sensitive factor (NSF), a critical regulator of vesicular dependent protein trafficking, as measured by in vitro protein binding and co-immunoprecipitation assays. In addition, we established that NSF interacts with residues 395-415 of the receptor beta subunits and co-localizes with GABA(A) receptors in hippocampal neurons. We also established that NSF can regulate GABA(A) receptor cell surface expression depending upon residues 395-415 in the beta 3 subunit. Together, our results suggest an important role for NSF activity in regulating the cell surface stability of GABA(A) receptors. (c) 2005 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.mcn.2005.07.006

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  • GABA(A) receptor phospho-dependent modulation is regulated by phospholipase C-related inactive protein type 1, a novel protein phosphatase 1 anchoring protein 査読

    M Terunuma, IS Jang, SH Ha, JT Kittler, T Kanematsu, JN Jovanovic, KI Nakayama, N Akaike, SH Ryu, SJ Moss, M Hirata

    JOURNAL OF NEUROSCIENCE   24 ( 32 )   7074 - 7084   2004年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOC NEUROSCIENCE  

    GABA(A) receptors are critical in controlling neuronal activity. Here, we examined the role for phospholipase C-related inactive protein type 1 (PRIP-1), which binds and inactivates protein phosphatase 1alpha (PP1alpha) in facilitating GABA(A) receptor phospho-dependent regulation using PRIP-1(-/-) mice. In wild-type animals, robust phosphorylation and functional modulation of GABA(A) receptors containing beta3 subunits by cAMP-dependent protein kinase was evident, which was diminished in PRIP-1(-/-) mice. PRIP-1(-/-) mice exhibited enhanced PP1alpha activity compared with controls. Furthermore, PRIP-1 was able to interact directly with GABA(A) receptor beta subunits, and moreover, these proteins were found to be PP1alpha substrates. Finally, phosphorylation of PRIP-1 on threonine 94 facilitated the dissociation of PP1alpha-PRIP-1 complexes, providing a local mechanism for the activation of PP1alpha. Together, these results suggest an essential role for PRIP-1 in controlling GABA(A) receptor activity via regulating subunit phosphorylation and thereby the efficacy of neuronal inhibition mediated by these receptors.

    DOI: 10.1523/JNEUROSCI.1323-04.2004

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  • The life cycle of the GABAA receptor and its regulating molecules 査読

    Takashi Kanematsu, Miho Terunuma, Hidefumi Goto, Akiko Kuratani, Masato Hirata

    Folia Pharmacologica Japonica   123 ( 2 )   105 - 112   2004年

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    記述言語:日本語  

    γ-Aminobutyric acidA (GABAA) receptors mediate most of the fast inhibitory neurotransmission in the central nervous system. These ligand-gated ion channels are crucial in the control of cell and network activity. Therefore, modulating their function or cell surface stability will have major consequences for neuronal excitation. This review highlights recent findings on the regulation of GABAA-receptor expression and function, focusing on the mechanisms of sorting, targeting, synaptic clustering, and endocytic events of GABAA receptors, all which are regulated by their associated proteins. Now these topics are an area of active interest in studies on inhibitory neurotransmission.

    DOI: 10.1254/fpj.123.105

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  • Interaction of p130 with, and consequent inhibition of, the catalytic subunit of protein phosphatase 1 alpha 査読

    K Yoshimura, H Takeuchi, O Sato, K Hidaka, N Doira, M Terunuma, K Harada, Y Ogawa, Y Ito, T Kanematsu, M Hirata

    JOURNAL OF BIOLOGICAL CHEMISTRY   276 ( 21 )   17908 - 17913   2001年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    The protein p130 was originally isolated from rat brain as an inositol 1,4,5-trisphosphate-binding protein with a domain organization similar to that of phospholipase C-delta1 but which lacks phospholipase C activity. Yeast two-hybrid screening of a human brain cDNA library for clones that encode proteins that interact with p130 has now led to the identification of the catalytic subunit of protein phosphatase 1 alpha (PP1c alpha) as a p130-binding protein. The association between p130 and PP1c alpha was also confirmed in vitro by an overlay assay, a "pull-down" assay, and surface plasmon resonance analysis. The interaction of p130 with PP1c alpha resulted in inhibition of the catalytic activity of the latter in a p130 concentration-dependent manner. Immunoprecipitation and immunoblot analysis of COS-1 cells that stably express p130 and of mouse brain extract with antibodies to p130 and to PP1c alpha also detected the presence of a complex of p130 and PP1c alpha, The activity of glycogen phosphorylase, which is negatively regulated by dephosphorylation by PP1c alpha, was higher in COS-1 cells that stably express p130 than in control COS-1 cells. These results suggest that, in addition to its role in inositol 1,4,5-trisphosphate and Ca2+ signaling, p130 might also contribute to regulation of protein dephosphorylation through its interaction with PP1c alpha.

    DOI: 10.1074/jbc.M009677200

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MISC

  • Phospho-dependent modulation of GABA(A) receptor by PRIP-1

    M Hirata, M Terunuma, T Kanematsu

    JOURNAL OF PHARMACOLOGICAL SCIENCES   97   88P - 88P   2005年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:JAPANESE PHARMACOLOGICAL SOC  

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  • 新規Ins(1.4,5)P3結合性タンパク質PRIP-1はGABAA受容体のリン酸化の調節に関わる

    兼松 隆, 照沼 美穂, 平田 雅人

    Journal of oral biosciences   46 ( 5 )   393 - 393   2004年9月

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    記述言語:日本語   出版者・発行元:歯科基礎医学会  

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  • Role of PRIP-1 involved in assembly, expression and regulation of GABA(A) receptor.

    T Kanematsu, M Terunuma, H Goto, A Kuratani, M Hirata

    JOURNAL OF PHARMACOLOGICAL SCIENCES   91   58P - 58P   2003年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:JAPANESE PHARMACOLOGICAL SOC  

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  • Regulation of phosphorylation of GABA(A) receptors by PRIP-1.

    M Terunuma, T Kanematsu, M Hirata

    JOURNAL OF PHARMACOLOGICAL SCIENCES   91   94P - 94P   2003年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:JAPANESE PHARMACOLOGICAL SOC  

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  • PRIP-1のIns(1,4,5)P3/Ca2+シグナリングにおける役割

    原田 佳枝, 竹内 弘, 照沼 美穂, 兼松 隆, 平田 雅人

    生化学   74 ( 8 )   915 - 915   2002年8月

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    記述言語:日本語   出版者・発行元:(公社)日本生化学会  

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  • イノシトールポリリン酸5‐ホスファターゼとプレックストリン相同領域の結合解析

    竹内弘, 原田佳枝, 照沼美穂, 八木沢仁, 平田雅人

    生化学   73 ( 8 )   964   2001年8月

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    記述言語:日本語  

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共同研究・競争的資金等の研究

  • 抗不安モデルマウスを用いたストレス耐性神経回路の解明

    研究課題/領域番号:23K06804

    2023年4月 - 2026年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    飯田 和泉, 阿部 学, 照沼 美穂

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

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  • 新たな不安発症の分子基盤解明のための日丁共同研究

    研究課題/領域番号:22KK0140

    2022年10月 - 2026年3月

    制度名:科学研究費助成事業

    研究種目:国際共同研究加速基金(国際共同研究強化(B))

    提供機関:日本学術振興会

    照沼 美穂, 市木 貴子, 飯田 和泉

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    配分額:20150000円 ( 直接経費:15500000円 、 間接経費:4650000円 )

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  • 末梢神経損傷により途切れた神経回路の人工シナプスコネクターによる感覚再生への挑戦

    研究課題/領域番号:22K19615

    2022年6月 - 2025年3月

    制度名:科学研究費助成事業

    研究種目:挑戦的研究(萌芽)

    提供機関:日本学術振興会

    瀬尾 憲司, 前田 健康, 岸本 直隆, 照沼 美穂, 武内 恒成

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    配分額:6370000円 ( 直接経費:4900000円 、 間接経費:1470000円 )

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  • 新規器官培養法による乳歯由来ヒトiPS細胞を経由したインスリン分泌細胞形成の誘導

    研究課題/領域番号:22H03277

    2022年4月 - 2025年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    齊藤 一誠, 佐藤 正宏, 野口 洋文, 照沼 美穂, 稲田 絵美, 薗村 貴弘

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    配分額:17420000円 ( 直接経費:13400000円 、 間接経費:4020000円 )

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  • 歯周病原細菌感染症としての精神疾患発症機構の解明

    研究課題/領域番号:21H03109

    2021年4月 - 2024年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    照沼 美穂, 多部田 康一, 飯田 和泉

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    配分額:17550000円 ( 直接経費:13500000円 、 間接経費:4050000円 )

    歯周病は口腔内感染症の一つであり、グラム陰性嫌気性菌であるPorphyromonas gingivalis菌(Pg菌)を含むいくつかの口腔内細菌が炎症を惹起することで発症すると考えられている。アルツハイマー病(AD)、パーキンソン病、うつ病などの精神・神経疾患は、脳の炎症所見である神経炎症が認められる疾患であり、感染症の1つである歯周病との関連性が報告されてきた。しかし、歯周病原細菌感染による脳疾患発症の病態生理学的な分子機序の解明は十分になされていない。最近、AD患者の脳からPg菌の16s rRNAやPg菌産生タンパク質分解酵素ジンジパインが検出された (Dominy et al, Science Advances, 2019)。口腔内細菌は、歯科治療や歯磨きなどでも血液中に侵入し、菌血症を発症させることから、本研究では、「血管内に侵入したPg菌は脳に作用する」との仮説を立て、検証を行うこととした。中でも、精神疾患との関連性を明らかにするために、ストレス反応の中枢であり、摂食行動や睡眠、性行動などの本能行動を司る視床下部に着目し研究を行う予定である。
    本年度は、尾静脈に投与したPg菌の追跡を行うために、細菌の生存時間について、経時的に解析をした。また、Pg菌の投与回数による脳の炎症反応の変化を、様々な部位において解析した。同時に、食欲や体重の変化の有無、基本的な行動解析を行い、マウスの健康状態を確認した。
    これらの研究により、Pg菌がどのような脳部位で著明な炎症反応を起こすかが明らかとなった。

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  • 脳梗塞における摂食嚥下障害の病態解明とその回復に顎口腔機能がもたらす効果

    研究課題/領域番号:21H03128

    2021年4月 - 2024年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    井上 誠, 辻村 恭憲, 那小屋 公太, 照沼 美穂, 吉原 翠, 真柄 仁

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    配分額:17290000円 ( 直接経費:13300000円 、 間接経費:3990000円 )

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  • 規格化ナノ構造チタンによる接着蛋白質を介した組織形成制御可能な生体材料開発

    研究課題/領域番号:21K09976

    2021年4月 - 2024年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    秋葉 陽介, 魚島 勝美, 照沼 美穂, 水野 潤, 泉 健次

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

    デンタルインプラントにおいては、オッセオインテグレーションと呼ばれるチタンと骨の結合が認められる。インプラントの成功基準の一つにオッセオインテグレーションの確立、成立が上げられている。臨床的には、デンタルインプラント表面をエッチングやサンドブラストによって粗造化することによって、骨芽細胞の接着、分化、骨形成を促進することができるとされている。しかし、チタン表面の粗造化がどのような構造因子と、それを認識し得る、細胞のどのような機能で細胞分化を促進するのか、といった詳細なメカニズムについては、十分な理解が進んでしない。これまでの研究において、粗造化されたチタンにおける、骨骨芽細胞の分化促進機構を検証する際に使用されていた、研磨による平滑な無構造チタンとされているチタンにおいても、電子顕微鏡下では、研磨に伴う研磨痕が多く観察され、細胞、タンパク質レベルでは無構造ではなく極めて粗造な構造が認識されていると考えられる。しかし、チタンに規格化され、制御された構造をナノレベルで形成することは、技術的に困難である。これまでの研究においては、数百ナノメートルの非規格化構造や規格化構造であっても数マイクロのサイズでしか構造形成は実現できていない。本研究においては、表面粗さ数ナノメートルの無構造チタン基板を基本に、構造因子に影響されないチタン特異的接着タンパク質群を同定し、さらに粗面構造における接着タンパク質群を同定し、構造因子による骨芽細胞接着分化促進因子を同定するものである。規格化ナノ構造チタンにおいては規格化線状ナノ構造を形成したチタン基板上での細胞挙動、組織形成制御を確認するために、骨髄由来細胞を播種培養し、ナノ構造によって細胞活動が制御され得ることを確認済みである。また、無構造チタン基板上において、接着タンパク質群の回収及び解析を実施している。

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  • アルコール摂取がもたらす認知機能障害の分子基盤

    研究課題/領域番号:18KK0258

    2018年10月 - 2022年3月

    制度名:科学研究費助成事業

    研究種目:国際共同研究加速基金(国際共同研究強化(B))

    提供機関:日本学術振興会

    照沼 美穂, 岸川 咲吏, 飯田 和泉

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    配分額:17940000円 ( 直接経費:13800000円 、 間接経費:4140000円 )

    慢性的なアルコール摂取は、肝機能障害による高アンモニア血症を発症させる。研究代表者は、肝機能障害による高アンモニア血症が生じると、脳の恒常性維持に重要な役割を果たすアストロサイトに炎症反応が起こり、さらにアンモニアによる刺激がアストロサイト内でのアルツハイマー病原因因子アミロイドβの産生を誘導することを見出した。このアストロサイトによるアミロイドβの産生機序を調べたところ、アストロサイトの細胞膜に発現するアミロイド前駆タンパク質APPが細胞内に取り込まれ、小胞体に輸送されることで起きることを突き止めた。この機構は新規アルツハイマー病発症機構であるとして、米国科学雑誌に発表した。

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  • 規格化ナノ構造に接着する蛋白質が制御する細胞機能の解明

    研究課題/領域番号:18K09679

    2018年4月 - 2021年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    秋葉 陽介, 照沼 美穂, 水野 潤, 泉 健次

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    配分額:4550000円 ( 直接経費:3500000円 、 間接経費:1050000円 )

    粒度の異なるチタン基板において、親水性と細胞増殖能が異なり、親水性と細胞増殖に関しては表面粗さ1.7nm、0.6nmのうち、0.6nmの超平滑基板では親水性は上昇したが、細胞増殖は表面粗さ1.7nmの基板に比較して低下した。また、細胞の配向性に関して、線状ナノ構造基板上で骨髄由来細胞を培養すると、細胞が細胞骨格、接着斑、分裂、伸長方向に配向性を持つことが観察されたが、この配向性つは、基板構造高さ100nm、50nmでは観察されたが25nm以下では観察されなかった。基板構造高さ25nmが細胞の増殖方向制御感受性の限界と考えられた。

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  • 神経伝達物質を起点とした癌根治療法の創出

    研究課題/領域番号:17K19748

    2017年6月 - 2019年3月

    制度名:科学研究費助成事業

    研究種目:挑戦的研究(萌芽)

    提供機関:日本学術振興会

    照沼 美穂, 山崎 学, 三上 剛和, 天谷 吉宏, 原田 史子

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    配分額:6370000円 ( 直接経費:4900000円 、 間接経費:1470000円 )

    がん抑制効果が期待されるAMPKと抑制性神経伝達を担うGABAB受容体のクロストークによる新しい抗がん剤の開発を目指すために研究を行った。その結果、口腔がん細胞に発現するGABAB受容体は脳細胞に発現するものとは異なり、その活性化による抗癌作用は確認できなかった。しかし、AMPKの活性化は単独で強力に抗癌作用を発揮した。今後その下流シグナルを標的とした、より特異的な分子の同定が必要である。

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  • 口腔粘膜上皮-小唾液腺ユニットを標的とした口腔乾燥治療の創薬応用

    研究課題/領域番号:17K12044

    2017年4月 - 2022年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    加藤 寛子, 照沼 美穂, 泉 健次

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    配分額:4550000円 ( 直接経費:3500000円 、 間接経費:1050000円 )

    副交感神経由来のアセチルコリンがムスカリン受容体に作用して唾液分泌は亢進する。現在、口腔乾燥症治療薬の適応はシェーグレン症候群や放射線治療後の口腔乾燥症などの特定の症例に限られているが、口腔乾燥が誘発する感染症等のリスク低減のためにも、広く適応を持つ有効な治療薬が必要である。申請者は口腔粘膜上皮組織には神経組織によらない非神経性コリン作動系のアセチルコリン産生システムが存在し、上皮細胞から分泌されるアセチルコリンが小唾液腺の唾液分泌を促進するという仮説を立て、研究を行った。

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  • 食欲中枢の制御機構と破綻の分子基盤の解明

    研究課題/領域番号:17H04372

    2017年4月 - 2020年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(B)

    提供機関:日本学術振興会

    照沼 美穂, 井上 誠, 竹林 浩秀, 南野 徹

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    配分額:17290000円 ( 直接経費:13300000円 、 間接経費:3990000円 )

    肥満や糖尿病を代表とするメタボリックシンドロームは、食欲の中枢である間脳の視床下部に炎症反応を引き起こし、食欲制御機構を破綻させる。原因として脳機能の安定化に不可欠なアストロサイトの変性と、付随する神経機能障害が挙げられるが、その分子機序は解明されていない。研究代表者はアストロサイトに特異的に発現するグルタミン合成酵素の調節を担う分子を同定したことから、視床下部アストロサイトにおいても重要な役割を果たしているか、さらにはこれらが食欲制御破綻の改善に役立つかを検討した。

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  • GABA受容体の機能的構築に関わる新しい分子に関する研究

    研究課題/領域番号:03J07823

    2003年 - 2004年

    制度名:科学研究費助成事業

    研究種目:特別研究員奨励費

    提供機関:日本学術振興会

    照沼 美穂

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    配分額:1800000円 ( 直接経費:1800000円 )

    GABA_A受容体β1-3サブユニット結合蛋白質PRIP-1がGABA_A受容体のリン酸化にどのような役割を果たしているかを解明するために以下の研究を行った。GABA_A受容体のリン酸化レベルを比較するために野生型、PRIP-1ノックアウト(PRIP-1^<-/->)マウスの海馬スライス標本を用いてPKAによるリン酸化を検討した。フォルスコリンで刺激したところ、PRIP-1^<-/->マウスでβ3サブユニットのS408/9のリン酸化が著明に減少していた。この原因を探るために、PKA活性を測定したところ違いは認められなかったが、PP1cαの活性がPRIP-1^<-/->マウスで約30%高かった。そこでPP1/PP2A活性阻害剤であるカリキュリンAやオカダ酸存在下にβ3サブユニットのリン酸化を検討したところ、PRIP-1^<-/->マウスでリン酸化レベルが回復した。また電気生理学的実験においても同様の結果が得られた。さらにPKAでリン酸化されたβ3サブユニットはPP1により著明に脱リン酸化されることも確認された。PRIP-1のリン酸化が脳細胞中でも起きるかを検討したところ、海馬、大脳皮質のいずれにおいてもリン酸化が観察され、さらにリン酸化によりPP1cαの結合が抑制された。PRIP-1のリン酸化部位を検索し、94番目のスレオニン(T94)、96番目のセリン(S96)がリン酸化残基であることを明らかにすると共にT94のリン酸化がPP1cαとの結合を制御していることも解明した。このことから、GABA_A受容体のPKAを介したリン酸化による機能的な調節にPRIP-1がPP1cαを受容体にリクルートする足場蛋白として関与していることをつきとめた。
    これらの結果はThe Journal of Neuroscience 24(32)20047074-7084に発表した。

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