Centers & Labs

RIKEN Brain Science Institute

Laboratory for Developmental Neurobiology

Laboratory Head: Katsuhiko Mikoshiba (M.D., Ph.D.)
Katsuhiko  Mikoshiba(M.D., Ph.D.)

The brain is composed of billions of neurons and glial cells, and their intimate communications are very important for the higher brain function. We are working to study how neuronal network is formed with the close functional interaction with glial cells. We are also studying how neuronal cells degenerate. One of the key factors to achieve their proper communication is "intracellular Ca2+ dynamics" in neurons and glial cells: neurons and glial cells translate intracellular Ca2+ dynamics into the activity of the signal transduction machineries, e.g. protein kinase and phosphatase, and subsequently modulate their intercellular communication. Since we identified and cloned IP3Rs in 1990s (Nature 1989) and found that it is a Ca2+ channel located at endoplasmic reticulum, It was essential to know the gating mechanism of IP3R channel. We recently succeeded in crystalizing the long cytoplasmic domain (2217 amino aid residues long) of IP3R in the presence and absence of IP3. We identified a long-range gating mechanism uncovered by channel mutagenes and X-ray crystallography of the large cytosolic domain of mouse type 1 IP3R in the presence of IP3. Analyses by X−ray crystallography uncovered an IP3-dependent global translocation of the curvature α-helical domain interfacing with the cytosolic and channel domains. We revealed an essential role of a leaflet structure in the α-helical domain that relays IP3-controlled global conformational dynamics to the channel. Many functional molecules associated with IP3Rs were located around the leaflet structure (PNAS 2017).
We have been focusing on the study of the role of IP3Rs and revealed the crucial role of IP3Rs in various physiological phenomena such as fertilization (Science 1992),dorso-ventral axis formation in early development (Cell 1993, 1996 J. Cell Biol., Nature 2002, Science 1997), synaptic plasticity (J. Neurosci. 2011, Nature 2000, Learning & Memory 2000, J. Neurosci.1998), neural circuit formation (Science 1998, Science Signaling 2009, J. Neurosci. 2011), dendrite formation (J. Neurosci. 2006) and spine formation (J. Neurosci. 2013, PNAS 2017) of neurons, and endocrine secretion(Science 2005). Our groups are going to further study the role of IP3Rs in the higher brain function (memory, emotion, locomotion) and brain diseases (schizophrenia, Huntington’s disease, Alzheimer disease and other ataxic diseases).
During the search for molecules biochemically associated with IP3R that may link the IP3R function. We demonstrated that the ER luminal protein ERp44 directly interacts with the luminal region of the type 1 IP3R and inhibits IP3R channel activity. The interaction is dependent on the pH, Ca2+ concentration, and redox state of the ER lumen (Cell, 2005). The IP3R/ERp44 system is thought to act as a molecular sensor that monitors the environment in the oxido-reduction of the ER lumen and transmits signals to the cytosolic space in living cells, perhaps acting as a quality control mechanism for protein biogenesis. We further discovered a chaperone, GRP78, which binds to the type 1 IP3R, and we consider that IP3R-GRP78 interaction may play an important role in apoptosis and in neurodegenerative diseases such as Alzheimer's or Huntington disease (Neuron 2010 used as a cover). We discovered a new molecule that was eluted with IP3 and we named it IRBIT (IP3R Binding protein released with Inositol 1,4,5-Trisphosphate). It is a homologue of S-adenosylhomocysteine hydrolase and has no enzyme activity. IRBIT was found to suppress IP3R activation by competing with IP3 as an endogenous pseudo-ligand (Molecular Cell 2006). We found that IRBIT activates the pancreatic type Na+/HCO3- cotransporter 1 (PNAS 2006) and that it also activates CFTR, chloride transporter (J. Clinical Investi. 2009, 2010). IRBIT inhibits CaMKIIα competing with Ca2+/CaM (PNAS 2015).
Moreover, we found that IP3R, IRBIT and Bcl2l10 associate in a complex in mitochondria-associated membranes (MAMs) and that their interplay is involved in apoptosis regulation. MAMs are a hotspot for Ca2+ transfer between endoplasmic reticulum (ER) and mitochondria, and massive Ca2+ release through IP3R in mitochondria induces cell death. We found that upon apoptotic stress, IRBIT is dephosphorylated, becoming an inhibitor of Bcl2l10.IRBIT promotes ER mitochondria contact. Our results suggest that by inhibiting Bcl2l10 activity and promoting contact between ER and mitochondria, IRBIT facilitates massive Ca2+ transfer to mitochondria and promotes apoptosis, suggesting that IRBIT as a new regulator of cell death. (eLife 2016).
IP3R/Ca2+ signaling is a funcamental mechanism for cell function. We are interested in the molecular mechanism how the complex spatio-temporal patterns of Ca2+ dynamics e.g. Ca2+ waves and Ca2+ oscillations that are generated in various types of cells. We are developing various indicators for IP3, Ca2+, apoptosis to measure cytosolic IP3 and Ca2+ (Nature Methods 2010)(J. Cell Biol. 2006) to detect subltle changes at any subcellular organella to decode the signals, which may cause pathophysiological condition of cells.. We are introducing various physico-chemical techniques such as electrophysiology, fluorescence imaging, and single molecule imaging, in addition to molecular, cellular and structure biology to understand the highly complex brain function and other complex functions of various organs.

Main Research Field

Biological Sciences

Related Research Fields

Complex systems / Interdisciplinary science and engineering / Biology / Medicine, dentistry, and pharmacy

Keywords

  • Development, Differentiation and Neural plasticity of the brain
  • Intracellular signal transduction in living cells
  • Molecular imaging of functional molecules in cells
  • Homeostasis of living body and its dysregulation
  • Structure and functional analysis of functional molecules in cells

Selected Publications

  1. Hamada K, Miyatake H, Terauchi A, Mikoshiba K.
    "IP3-mediated gating mechanism of the IP3 receptor revealed by mutagenesis and X-ray crystallography"
    Proc Natl Acad Sci U S A. 114(18): 4661-4666. (2017)
  2. Sugawara T. Hisatsune C, Miyamoto H, Ogawa N, Mikoshiba K.
    "Regulation of spinogenesis in mature Purkinje cells via mGluR/PKC-mediated phosphorylation of CaMKII"
    Proc Natl Acad Sci U S A. 114(26): E5256-E5265. (2017)
  3. Kawaai K, Ando H, Satoh N, Yamada H, Ogawa N, Hirose M, Mizutani A, Bonneau B, Seki G, Mikoshiba K.
    "Splicing variation of Long-IRBIT determines the target selectivity of IRBIT family proteins."
    Proc Natl Acad Sci U SA. 114(15): 3921-3926. (2017)
  4. Yamada Y., *Matsumoto (*equal contribution)Y., Okahara N., and Mikoshiba K.
    "Chronic multiscale imaging of neuronal activity in the awake common marmoset."
    Scientific Reports 6: 35722 (2016)
  5. Bonneau B, Ando H, Kawaai K, Hirose M, Takahashi-Iwanaga H, Mikoshiba K.
    "IRBIT controls apoptosis by interacting with the Bcl-2 homolog, Bcl2l10, and by promoting ER-mitochondria contact."
    eLife 19896. (2016)
  6. Monai H, Ohkura M, Tanaka M, Oe Y, Konno A, Hirai H, Mikoshiba K, Itohara S, Nakai J, Iwai Y, Hirase H.
    "Calcium imaging reveals glial involvement in transcranial direct current stimulation-induced plasticity in mouse brain."
    Nature Communications 7: 11100 (2016)
  7. Bannai H, Niwa F, Sherwood M.W, Shrivastava A.N, Arizono M, Miyamoto A, Sugiura K, Lévi S, TrillerA, Mikoshiba K
    "Bidirectional control of synaptic GABAAR clustering by glutamate and calcium."
    Cell Reports 13:1-3 (2015)
  8. Hisatsune C, Ebisui E, Usui M, Ogawa N, Suzuki A, Mataga N, Takahashi-Iwanaga H, Mikoshiba K.
    "ERp44 Exerts Redox-Dependent Control of Blood Pressure at the ER."
    Molecular Cell. S1097-2765(15)00264-6. (2015)
  9. Kawaai K, Mizutani A, Shoji H, Ogawa N, Ebisui E, Kuroda Y, Wakana S, Miyakawa T, Hisatsune C, Mikoshiba K.
    "IRBIT regulates CaMKIIα activity and contributes to catecholamine homeostasis through tyrosine hydroxylase phosphorylation."
    Proc Natl Acad Sci U S A. 112(17): 5515-20. (2015)
  10. Tsuboi D, Kuroda K, Tanaka M, Namba T, Iizuka Y, Taya S, Shinoda T, Hikita T, Muraoka S, Iizuka M, Nimura A, Mizoguchi A, Shiina N, Sokabe M, Okano H, Mikoshiba K, and Kaibuchi K.
    "Disrupted-in-Schizophrenia-1 regulates transport of IP3R1 mRNA for synaptic plasticity."
    Nature Neurosci. 18(5): 698-707. (2015)

Lab Members

Principal Investigator

Katsuhiko Mikoshiba
Laboratory Head

Core Members

Kozo Hamada
Research Scientist
Chihiro Hisatsune
Research Scientist
Hiroyuki Kabayama
Research Scientist
Hideaki Ando
Research Scientist
Katsuhiro Kawaai
Research Scientist
Akitoshi Miyamoto
Research Scientist
Takeyuki Sugawara
Research Scientist
Yoshifumi Matsumoto
Research Scientist
Benjamin Remi Bonneau
Special Postdoctoral Researcher
Matsumi Hirose
Technical Staff I
Etsuko Ebisui
Technical Staff I
Naoko Tokushige
Technical Staff I
Akiko Terauchi
Technical Staff I
Naoko Ogawa
Technical Staff I
Makoto Takeuchi
Technical Staff I
Kotomi Sugiura
Technical Staff I

Contact information

2-1 Hirosawa, Wako, Saitama 351-0198, Japan
Tel: +81-(0)48-467-9745
Fax: +81-(0)48-467-9744

Email: mikosiba [at] brain.riken.jp

Related links

Recent research results