記述言語：英語   掲載種別：研究論文（学術雑誌）  

Plasticity of synaptic transmission underlies learning and memory. It is accompanied by changes in the density and size of synapses, collectively called structural plasticity. Therefore, understanding the mechanism of structural plasticity is critical for understanding the mechanism of synaptic plasticity. In this chapter, we describe the procedures and equipment required to image structural plasticity of a single dendritic spine, which hosts excitatory synapses in the central nervous system, and underlying molecular interactions/biochemical reactions using two-photon fluorescence lifetime microscopy (2P-FLIM) in combination with Förster resonance energy transfer (FRET)-based biosensors.

DOI： 10.1007/978-1-0716-3969-6_14

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Synaptic plasticity plays a crucial role in memory formation by regulating the communication between neurons. Although actin polymerization has been linked to synaptic plasticity and dendritic spine stability, the causal link between actin polymerization and memory encoding has not been identified yet. It is not clear whether actin polymerization and structural changes in dendritic spines are a driver or a consequence of learning and memory. Using an extrinsically disordered form of the protein kinase LIMK1, which rapidly and precisely acts on ADF/cofilin, a direct modifier of actin, we induced long-term enlargement of dendritic spines and enhancement of synaptic transmission in the hippocampus on command. The activation of extrinsically disordered LIMK1 in vivo improved memory encoding and slowed cognitive decline in aged mice exhibiting reduced cofilin phosphorylation. The engineered memory by an extrinsically disordered LIMK1 supports a direct causal link between actin-mediated synaptic transmission and memory.

DOI： 10.1126/sciadv.adh1110

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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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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Interactions between an enzyme kinase, an ion channel and cytoskeletal proteins maintain the structure of synapses involved in memory formation.

DOI： 10.7554/eLife.91566

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a signaling protein required for long-term memory. When activated by Ca2+/CaM, it sustains activity even after the Ca2+ dissipates. In addition to the well-known autophosphorylation-mediated mechanism, interaction with specific binding partners also persistently activates CaMKII. A long-standing model invokes two distinct S and T sites. If an interactor binds at the T-site, then it will preclude autoinhibition and allow substrates to be phosphorylated at the S site. Here, we specifically test this model with X-ray crystallography, molecular dynamics simulations, and biochemistry. Our data are inconsistent with this model. Co-crystal structures of four different activators or substrates show that they all bind to a single continuous site across the kinase domain. We propose a mechanistic model where persistent CaMKII activity is facilitated by high-affinity binding partners that kinetically compete with autoinhibition by the regulatory segment to allow substrate phosphorylation.

DOI： 10.1016/j.celrep.2022.111064

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Dendritic spines constitute the major compartments of excitatory post-synapses. They undergo activity-dependent enlargement, which is thought to increase the synaptic efficacy underlying learning and memory. The activity-dependent spine enlargement requires activation of signaling pathways leading to promotion of actin polymerization within the spines. However, the molecular machinery that suffices for that structural plasticity remains unclear. Here, we demonstrate that shootin1a links polymerizing actin filaments in spines with the cell-adhesion molecules N-cadherin and L1-CAM, thereby mechanically coupling the filaments to the extracellular environment. Synaptic activation enhances shootin1a-mediated actin-adhesion coupling in spines. Promotion of actin polymerization is insufficient for the plasticity; the enhanced actin-adhesion coupling is required for polymerizing actin filaments to push against the membrane for spine enlargement. By integrating cell signaling, cell adhesion, and force generation into the current model of actin-based machinery, we propose molecular machinery that is sufficient to trigger the activity-dependent spine structural plasticity.

DOI： 10.1016/j.celrep.2021.109130

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Synaptic connections in neuronal circuits change in response to neuronal activity patterns. This can induce a persistent change in the efficacy of synaptic transmission, a phenomenon known as synaptic plasticity. One form of plasticity, long-term potentiation (LTP) has been extensively studied as the cellular basis of memory. In LTP, the potentiated synaptic transmission persists along with structural changes in the synapses. Many studies have sought to identify the "memory molecule" or the "molecular engram". Ca2+/calmodulin-dependent protein kinase II (CaMKII) is probably the most well-studied candidate for the memory molecule. However, consensus has not yet been reached on a very basic aspect: how CaMKII is regulated during LTP. Here, I propose a new model of CaMKII regulation: reciprocal activation within a kinase effector complex (RAKEC) that is made between CaMKII and its effector protein, which is mediated by a persistent interaction between CaMKII and a pseudosubstrate sequence on T-lymphoma invasion and metastasis protein 1 (Tiam1), resulting in reciprocal activation of these two molecules. Through the RAKEC mechanism, CaMKII can maintain memory as biochemical activity in a synapse-specific manner. In this review, the detailed mechanism of the RAKEC and its expansion for the maintenance of LTP is described.

DOI： 10.1016/j.brainresbull.2021.01.018

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.biopsych.2019.06.002

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.nlm.2019.107070

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.neuron.2019.04.012

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Glutathione-labile protecting groups for phosphodiester moieties in oligonucleotides were designed, synthesized, and incorporated into oligonucleotides. The protecting groups on the phosphodiester moieties were cleaved in a buffer containing 10 mM glutathione, which was used as a model of intracellular fluid. Cellular uptake of oligonucleotides bearing glutathione-labile protecting groups was strongly affected by the location and number of the protecting groups.

DOI： 10.1021/acs.orglett.8b03501

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/ijms19072008

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記述言語：英語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/jnc.13672

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1021/acs.bioconjchem.6b00368

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掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0116319

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/embj.201488619

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.neuron.2014.03.021

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/cm.21037

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s11060-010-0472-6

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.conb.2009.09.013

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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.1544-09.2009

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.neuron.2007.11.016

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.neuron.2006.05.008

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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.4086-04.2005

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1074/jbc.M409873200

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/S1096-4959(02)00292-0

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/417295a

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Equine FSH (eFSH) and eCG are members of the glycoprotein hormone family. These proteins are heterodimeric, composed of noncovalently associated α and β subunits. We have previously reported that recombinant eCG has potent LH- and FSH-like activities and that the oligosaccharide at Asn16of the α subunit plays an indispensable role in expressing LH- but not FSH-like activity. In the present study, we cloned eFSH β subunit cDNA and expressed wild-type recombinant eFSH and a partially deglycosylated mutant FSH (eFSH α56/β) to investigate the biological role of the oligosaccharide at Asn16in FSH activity. The wild-type eFSH and eCG stimulated estradiol production in a dose-dependent manner in the primary cultures of rat granulosa cells, indicating that these equine gonadotropins have FSH activity. Partially deglycosylated eCG (eCG α56/β) also stimulated estradiol production, confirming that the FSH-like activity of eCG is resistant to the removal of the N-linked oligosaccharide. Partially deglycosylated eFSH (eFSH α56/β), however, did not show any FSH activity, indicating that the oligosaccharide at Asn56was necessary for eFSH. Thus, FSH-like activities of two gonadotropins, eCG and eFSH, are evoked through the distinct molecular mechanisms regarding the biological role of oligosaccharide at Asn56of the αsubunit.

DOI： 10.1095/biolreprod65.6.1686

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/S0167-4889(00)00083-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1046/j.1440-169X.2000.00519.x

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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）  

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