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

• Project/Area Number: 16K07075
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Keio University (2018); Institute of Physical and Chemical Research (2016-2017)
• Principal Investigator: Kawaai Katsuhiro 慶應義塾大学, 医学部(信濃町), 助教 (00553653)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: IRBIT / LongIRBIT / pH / 塩素イオン / Splicing variants / 多機能性蛋白質 / 神経可塑性 / カルシウム / splicing varinats / 神経科学

Outline of Final Research Achievements

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.

Academic Significance and Societal Importance of the Research Achievements

IRBITファミリーの標的分子選択機構の一つとして、スプライシングによる部分配列変化とヘテロ多量体形成の組み合わせによる多様性という新たな制御機構を示した。このことは、様々な分子と相互作用することで多様な生命現象に寄与する多機能性分子が、いかにして標的分子を選択し、適切な生命活動を担うのかという分子生物学の本質的問いに新たな知見を与えるものと考える。また、AEは原発性胆汁性肝硬変や尿生殖路の自己免疫疾患、QT短縮症候群や白内障との関連が報告されている。CaCCに関しては前頭洞癌との関連が報告されており、これら疾患の発症機序解明の新たな糸口となる可能性がある。

Research Products

• [Journal Article] Trans-pairing between osteoclasts and osteoblasts shapes the cranial base during development. (2019)
  • Author(s): Edamoto M, Kuroda Y, Yoda M, Kawaai K, Matsuo K.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 297-297
  • DOI: 10.1038/s41598-018-38471-w
  • Peer Reviewed / Open Access
• [Journal Article] Bone (2019)
  • Author(s): Matsuo K, Ji S, Miya A, Yoda M, Hamada Y, Tanaka T, Takao-Kawabata R, Kawaai K, Kuroda Y, Shibata S.
  • Journal Title: Innervation of the tibial epiphysis through the intercondylar foramen. Volume: 120 Pages: 297-304
  • DOI: 10.1016/j.bone.2018.11.007
  • Peer Reviewed / Open Access
• [Journal Article] Remodeling of Ca2+ signaling in cancer: Regulation of inositol 1,4,5-trisphosphate receptors through oncogenes and tumor suppressors. (2017)
  • Author(s): Ando H, Kawaai K, Bonneau B, Mikoshiba K.
  • Journal Title: Adv Biol Regul. Volume: pii: S2212-4926(17) Pages: 30188-4
  • DOI: 10.1016/j.jbior.2017.12.001
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Splicing variation of Long-IRBIT determines the target selectivity of IRBIT family proteins. (2017)
  • Author(s): Kawaai K, Ando H, Satoh N, Yamada H, Ogawa N, Hirose M, Mizutani A, Bonneau B, Seki G, Mikoshiba K.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 114(15) Issue: 15 Pages: 3921-3926
  • DOI: 10.1073/pnas.1618514114
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] IRBIT controls apoptosis by interacting with the Bcl-2 homolog, Bcl2l10, and by promoting ER-mitochondria contact (2016)
  • Author(s): Bonneau B, Ando H, Kawaai K, Hirose M, Takahashi-Iwanaga H, Mikoshiba K.
  • Journal Title: Elife Volume: e19896 Pages: 1-27
  • DOI: 10.7554/elife.19896
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Splicing variation of Long-IRBIT determines the target selectivity of IRBIT family (2017)
  • Author(s): Kawaai K, Ando H, Satoh N, Yamada H, Ogawa N, Hirose M, Mizutani A, Bonneau B, Seki G, Mikoshiba K.
  • Organizer: 第60回日本神経化学会大会