Kawaai, Katsuhiro



School of Medicine, Center for Integrated Medical Research (Shinanomachi)



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Books 【 Display / hide

  • 分子細胞生物学辞典, 第2版

    河合克宏, 東京化学同人, 2008.10

    Scope: 「4.1」「ドーパミントランスポーター」「Parkin」「Pax」「VEGF受容体」「スクランブラーマウス」「ヨタリマウス」「disabled homolog 1」「リーラーマウス」「小脳プルキンエ細胞欠失ミュータントマウス」「スタゲラーマウス」「ナーバスマウス」「pcdマウス」「シナプス後肥厚部」「バーグマングリア」

Papers 【 Display / hide

  • Transient appearance of Ca2+ -permeable AMPA receptors is crucial for the production of repetitive LTP-induced synaptic enhancement (RISE) in cultured hippocampal slices.

    Keiko Tominaga-Yoshino, Tomoyoshi Urakubo, Yukiko Ueno, Katsuhiro Kawaai, Shinichi Saito, Tomoko Tashiro, Akihiko Ogura

    Hippocampus 30 ( 7 ) 763 - 769 2020.04

    Joint Work, Accepted,  ISSN  1050-9631

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    We have previously shown that repetitive induction of long-term potentiation (LTP) by glutamate (100 μM, 3 min, three times at 24-hr intervals) provoked long-lasting synaptic enhancement accompanied by synaptogenesis in rat hippocampal slice cultures, a phenomenon termed RISE (repetitive LTP-induced synaptic enhancement). Here, we examined the role of Ca2+ -permeable (CP) AMPA receptors (AMPARs) in the establishment of RISE. We first found a component sensitive to the Joro-spider toxin (JSTX), a blocker of CP-AMPARs, in a field EPSP recorded from CA3-CA1 synapses at 2-3 days after stimulation, but this component was not found for 9-10 days. We also observed that rectification of AMPAR-mediated current appeared only 2-3 days after stimulation, using a whole-cell patch clamp recording from CA1 pyramidal neurons. These findings indicate that CP-AMPAR is transiently expressed in the developing phase of RISE. The blockade of CP-AMPARs by JSTX for 24 hr at this developing phase inhibited RISE establishment, accompanied by the loss of small synapses at the ultrastructural level. These results suggest that transiently induced CP-AMPARs play a critical role in synaptogenesis in the developing phase of long-lasting hippocampal synaptic plasticity, RISE.

  • Trans-pairing between osteoclasts and osteoblasts shapes the cranial base during development.

    Edamoto M, Kuroda Y, Yoda M, Kawaai K, Matsuo K

    Scientific reports (Scientific Reports)  9 ( 1 ) 1956 2019.12

    Joint Work, Accepted

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    © 2019, The Author(s). Bone growth is linked to expansion of nearby organs, as is the case for the cranial base and the brain. Here, we focused on development of the mouse clivus, a sloping surface of the basioccipital bone, to define mechanisms underlying morphological changes in bone in response to brain enlargement. Histological analysis indicated that both endocranial and ectocranial cortical bone layers in the basioccipital carry the osteoclast surface dorsally and the osteoblast surface ventrally. Finite element analysis of mechanical stress on the clivus revealed that compressive and tensile stresses appeared mainly on respective dorsal and ventral surfaces of the basioccipital bone. Osteoclastic bone resorption occurred primarily in the compression area, whereas areas of bone formation largely coincided with the tension area. These data collectively suggest that compressive and tensile stresses govern respective localization of osteoclasts and osteoblasts. Developmental analysis of the basioccipital bone revealed the clivus to be angled in early postnatal wild-type mice, whereas its slope was less prominent in Tnfsf11 −/− mice, which lack osteoclasts. We propose that osteoclast-osteoblast “trans-pairing” across cortical bone is primarily induced by mechanical stress from growing organs and regulates shape and size of bones that encase the brain.

  • Innervation of the tibial epiphysis through the intercondylar foramen.

    Matsuo K, Shuting J, Miya A, Yoda M, Hamada Y, Tanaka T, Takao-Kawabata R, Kawaai K, Kuroda Y, Shibata S

    Bone (Bone)  120   297 - 304 2019.03

    Joint Work, Accepted,  ISSN  87563282

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    © 2018 The Authors The periosteum and mineralized bone are innervated by nerves that sense pain. These include both myelinated and unmyelinated neurons with either free nerve endings or bearing nociceptors. Parasympathetic and sympathetic autonomic nerves also innervate bone. However, little is known about the route sensory nerves take leaving the epiphyses of long bones at the adult knee joint. Here, we used transgenic mice that express fluorescent Venus protein in Schwann cells (Sox10-Venus mice) to visualize myelinated and unmyelinated nerves in the tibial epiphysis. Immunofluorescence to detect a pan-neuronal marker and the sensory neuron markers calcitonin gene-related peptide (CGRP) and tropomyosin receptor kinase A (TrkA) also revealed Schwann cell-associated sensory neurons. Foramina in the intercondylar area of the tibia were conserved between rodents and primates. Venus-labeled fibers were detected within bone marrow of the proximal epiphysis, exited through foramina along with blood vessels in the intercondylar area of the tibia, and joined Venus-labeled fibers of the synovial membrane and meniscus. These data suggest that innervation of the subchondral plate and trabecular bone within the tibial epiphysis carries pain signals from the knee joint to the brain through intercondylar foramina.

  • Remodeling of Ca2+ signaling in cancer: Regulation of inositol 1,4,5-trisphosphate receptors through oncogenes and tumor suppressors.

    Ando H, Kawaai K, Bonneau B, Mikoshiba K

    Advances in biological regulation (Advances in Biological Regulation)  68   64 - 76 2018.05

    Joint Work, Accepted,  ISSN  22124926

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    © 2017 Elsevier Ltd The calcium ion (Ca2+) is a ubiquitous intracellular signaling molecule that regulates diverse physiological and pathological processes, including cancer. Increasing evidence indicates that oncogenes and tumor suppressors regulate the Ca2+ transport systems. Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) are IP3-activated Ca2+ release channels located on the endoplasmic reticulum (ER). They play pivotal roles in the regulation of cell death and survival by controlling Ca2+ transfer from the ER to mitochondria through mitochondria-associated ER membranes (MAMs). Optimal levels of Ca2+ mobilization to mitochondria are necessary for mitochondrial bioenergetics, whereas excessive Ca2+ flux into mitochondria causes loss of mitochondrial membrane integrity and apoptotic cell death. In addition to well-known functions on outer mitochondrial membranes, B-cell lymphoma 2 (Bcl-2) family proteins are localized on the ER and regulate IP3Rs to control Ca2+ transfer into mitochondria. Another regulatory protein of IP3R, IP3R-binding protein released with IP3 (IRBIT), cooperates with or counteracts the Bcl-2 family member depending on cellular states. Furthermore, several oncogenes and tumor suppressors, including Akt, K-Ras, phosphatase and tensin homolog (PTEN), promyelocytic leukemia protein (PML), BRCA1, and BRCA1 associated protein 1 (BAP1), are localized on the ER or at MAMs and negatively or positively regulate apoptotic cell death through interactions with IP3Rs and regulation of Ca2+ dynamics. The remodeling of Ca2+ signaling by oncogenes and tumor suppressors that interact with IP3Rs has fundamental roles in the pathology of cancers.

  • Splicing variation of Long-IRBIT determines the target selectivity of IRBIT family proteins

    Kawaai Katsuhiro, Ando Hideaki, Satoh Nobuhiko, Yamada Hideomi, Ogawa Naoko, Hirose Matsumi, Mizutani Akihiro, Bonneau Benjamin, Seki George, Mikoshiba Katsuhiko

    Proceedings of the National Academy of Sciences of the United States of America (NATL ACAD SCIENCES)  114 ( 15 ) 3921 - 3926 2017

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  0027-8424

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    IRBIT [inositol 1,4,5-trisphosphate receptor (IP3R) binding protein released with inositol 1,4,5-trisphosphate (IP3)] is a multifunctional protein that regulates several target molecules such as ion channels, transporters, polyadenylation complex, and kinases. Through its interaction with multiple targets, IRBIT contributes to calcium signaling, electrolyte transport, mRNA processing, cell cycle, and neuronal function. However, the regulatory mechanism of IRBIT binding to particular targets is poorly understood. Long-IRBIT is an IRBIT homolog with high homology to IRBIT, except for a unique N-terminal appendage. Long-IRBIT splice variants have different N-terminal sequences and a common C-terminal region, which is involved in multimerization of IRBIT and Long-IRBIT. In this study, we characterized IRBIT and Long-IRBIT splice variants (IRBIT family). We determined that the IRBIT family exhibits different mRNA expression patterns in various tissues. The IRBIT family formed homo-and heteromultimers. In addition, N-terminal splicing of Long-IRBIT changed the protein stability and selectivity to target molecules. These results suggest that N-terminal diversity of the IRBIT family and various combinations of multimer formation contribute to the functional diversity of the IRBIT family.

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Papers, etc., Registered in KOARA 【 Display / hide

Reviews, Commentaries, etc. 【 Display / hide

  • IRBITは脂肪細胞分化初期の細胞増殖を制御している

    関口藍理, 浜田浩一, 佐藤聖子, 高橋透泰, 下田沙弥, 波多野直哉, 河合克宏, 御子柴克彦, 水谷顕洋

    聖マリアンナ医科大学雑誌(Web) (聖マリアンナ医科大学医学会)  44 ( 3 ) 183 (WEB ONLY) - 183 2016.11

    Other, Joint Work,  ISSN  2189-0285

Presentations 【 Display / hide

  • 内軟骨性骨化における軟骨原基と骨の関係 -タルボX線位相トモグラフィー顕微鏡による形態解析-

    松尾光一, 姫シュウテイ, 黒田有希子, 河合克宏, 呉彦霖, 高野秀和, 百生敦



    Poster presentation

  • 内軟骨性骨化で形成される耳小骨は軟骨原基より小さい

    姫しゅうてい, 黒田有希子, 河合克宏, 百生 敦, 松尾光一



    Oral presentation (general)

  • 超石灰化骨芽細胞によって形成された骨は II 型コラー ゲンを含み骨密度が高くなる

    黒田有希子, 河合克宏, 松尾光一



    Oral presentation (general)

  • Osteoclast-Osteoblast "Trans-pairing" across Cortical Bone Shapes Developing Long Bones

    Koichi Matsuo, Masaki Yoda, Yukiko Kuroda, Katsuhiro Kawaai, Yanlin Wu, Hidekazu Takano, Atsushi Momose

    The American Society for Bone and Mineral Research 2019, 


    Poster presentation

  • Splicing variation of Long-IRBIT determines the target selectivity of IRBIT family.

    Kawaai K, Ando H, Satoh N, Yamada H, Ogawa N, Hirose M, Mizutani A, Bonneau B, Seki G, Mikoshiba K.



    Poster presentation

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Research Projects of Competitive Funds, etc. 【 Display / hide

  • Elucidation of the mechanisms for bone destruction in chordoma.


    MEXT,JSPS, Grant-in-Aid for Scientific Research, 基盤研究(C), Principal investigator

  • 骨芽細胞動態解析による軟骨原基を起点とした骨形成過程の解明と応用


    Keio University, Grant-in-Aid for Scientific Research (C), No Setting

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  • Regulation of intracellular pH and chloride changes by IRBIT family in neurons.


    Institute of Physical and Chemical Research, Kawaai Katsuhiro, Grant-in-Aid for Scientific Research (C), No Setting

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    We identified anion exchanger (AE) and calcium dependent chloride channel (CaCC) as novel IRBIT family interacting molecule and found that IRBIT family regulates the activity of AE and CaCC. IRBIT, Long-IRBIT, AE, and CaCC were expressed in hippocampal neurons. We also found that the intracellular pH and chloride changes were impaired in hippocampal neurons, which were derived from IRBIT or Long-IRBIT knockout mouse.
    In addition, we found that IRBIT and Long-IRBIT splicing variants formed heteromultimers and N-terminal variation of Long-IRBIT by splicing affected protein stability and target selectivity. Thus, N-terminal variation of IRBIT family members mediates the regulation of multiple signaling pathways.

  • Clarifying the role of IRBIT in the coupling regulation of intracellular pH and Ca2+ in astrocytes.


    Showa Pharmaceutical University, MIZUTANI Akihiro, SEKI Jouji, KAWAAI Katsuhiro, Grant-in-Aid for Scientific Research (C), No Setting

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    IRBIT was in vitro phosphorylated by PKA on Ser62, Ser64, and Ser66, and the phosphorylations might be involved in the high affinity of high-phosphorylated IRBIT for IP3R. Indeed, IRBIT phosphorylated on Ser68, Ser71, Ser74 and Ser77 as well as on Ser62, Ser64,and Ser66 showed high-phosphorylated pattern revealed on Phos-Tag SDS-PAGE analysis. However, this densely phosphorylated IRBIT did not show high binding affinity to IP3R suggesting that additional phosphorylations on other sites or unidentified modifications are necessary for getting high affinity to IP3R.
    In SLC4A4 deficient mice, an expression level of IRBIT protein was drastically reduced, and IRBIT in a soluble fraction was increased. Moreover, IRBIT was massively phosphorylated showing high affinity for IP3R. These results suggested that IRBIT was indeed phosphorylated in an NBCe1 activity dependent manner and could couple the intracellular pH homeostasis and Ca2+ dynamics.

  • Analysis of the pathogenic mechanism for neuropsychiatric disease-like abnormal behavior in IRBIT knockout mouse


    独立行政法人理化学研究所, KAWAAI Katsuhiro, Grant-in-Aid for Young Scientists (B), No Setting

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    An IP3R binding protein termed IRBIT (IP3R binding protein released with inositol 1,4,5-trisphosphate) that interacts with the IP3 binding core domain of IP3R and regulate the IP3 sensitivity of IP3R. Recently, we identified calcium/calmodulin-dependent kinase II alpha (CaMKIIalpha) as an IRBIT binding protein. In this study, we investigated the effect of IRBIT deletion on the monoamine (dopamine and norepinephrine) synthesis and intracellular pH regulation to explain the function of IRBIT in the central nervous system. We found that IRBIT regulated the phosphoryaltion state of TH by CaMKIIalpha. In addition, IRBIT contributed the regulation of intracellular pH by NBC1 in the neuron and astrocyte.

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Courses Taught 【 Display / hide