Professor, Principal Investigator

Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University
Laboratory: Lab of Cell Calcium Signaling

Email: mikosiba@@shanghaitech.edu.cn

Education

1969   M.D. Keio University School of Medicine

1973   Ph.D. Keio University

Employments

1973-1974     Assistant Professor, Dept. of Physiology, Keio Univ. School of Medicine

1974-1982     Lecturer, Dept. of Physiology, Keio Univ. School of Medicine

1976-1977     Research Associate Pasteur Institute, Paris, France (c/o Prof. Jean-Pierre Changeux)

1982-1985     Associate Prof., Department of Physiology, Keio Univ. School of Medicine

1985-1992     Professor, Institute for Protein Research, Osaka University

1986-1991     Professor, National Institute for Basic Biology, Okazaki (Adjunct position)

1992-1997     Chief Scientist, Molecular Neurobiology Laboratory, RIKEN, Tsukuba (Adjunct position)

1992-2007     Professor, The Institute of Medical Science, The University of Tokyo

1998-2009     Team Leader, Group Director, RIKEN Brain Science Institute (BSI) (Adjunct position)

2003-2015      Foreign Professor (Adjunct Professor) at Karolinska Institute (received an honorary doctorate from Karolinska Institute)

2005-present  Member of Science Council of Japan

2007-present  Professor Emeritus of University of Tokyo

2008-2011      Foreign Professor of Seoul National University (Korea) (World Class University Professor, WCU Prof. program)

2009-2019      Senior Team Leader, Lab. for Developmental Neurobiol., BSI, RIKEN

2019-present  Professor, SIAIS (Shanghai Institute for Advanced Immunochemical Studies), ShanghaiTech University

Honors and Prizes

1974    Erwin von Bälz Preis

1980    Kitazato Prize

1987    The Inoue Scientific Prize

1987   The Memorial Prize for Tsukahara Nakaakira  (1^st memorial prize)

1991    The Osaka Prize for Science

1996    Medical Award of the Japan Medical Association

1996    Human Frontier Science Program Grant Award (1996-1998) with C,B.Wollheim as a team leader

1997    Uehara Prize

1998    The Keio Medical Science Prize (International Prize)

1999    Human Frontier Science Program Grant Award (1999-2001) with J.P.Changeux as a team leader

1999    The Fritz-Lipmann Lecture Award (Germany)

2000    College de France Medal (France)

2002    Medal of Honor in Japan (Medal with Purple Ribbon-Emperor’s Prize)

2003    Klaus Joachim Zülch-Preis (Germany Max-Planck Institute, Gertrud Reemtsma Foundation)

2003    Foreign Professor at Karolinska Institute (Adjunct Professor), (Sweden)

2004    Takeda Medical Science Prize (Takeda Foundation, Japan)

2005    Meister Prize (Endocrinology Society for Japan)

2006    Nobel Forum Lecture (Karolinska Institute, Sweden)

2007    Hagiwara Lecture (The Physiological Society of Japan)

2008    Sherrington Lecture (Liverpool, UK)

2009    The Naito Foundation Research Prize

2009    Japan Academy Prize (Emperor’s prize)

2010    Honorary Membership of the Japanese Biochemical Society

2011    Honorary Doctorate (Medical Doctor) at Karolinska Institute

             (Karolinska Institutet, Sweden).

2011    Honorary Membership of the European Calcium Society.

2013     Dr. Martin Rodbell Lecture (NIH-NIEHS),USA

2013    Special Prize, Scientist of the year 2013, of the International Society of Antioxidants in Nutrition and Health

2013    lOrder National de la Legion d`honneur ( grade de Chevalier, Knight)  (Republic of France)

2013    George and Catherine Weber Special Symposium Lecture (Bologna, Academy of Science, Italy)

2018    The Order of the Sacred Treasure, Gold Rays with Neck Ribbon (Emperor’s Honor)

Laboratory: Lab of Cell Calcium Signaling

Lab of Cell Calcium Signaling is a newly established Mikoshiba lab at ShanghaiTech University in April 1^st 2019.

Our lab studies the cellular and molecular mechanism of calcium signaling in the normal and disease states.  Intracellular calcium ions (Ca²⁺) must be kept under strict control at a very low level inside the cells so that Ca²⁺ can act as second messengers responsible for diverse cell functions. Massive Ca²⁺ increases in the cytosol are incompatible with cell survival and abnormal Ca²⁺ signaling results in various kinds of diseases. 

We discovered a key Ca²⁺ channel, inositol 1,4,5-trisphosphate (IP₃) receptor (Nature 1989) and found its role in fertilization (Science 1992), dorso-ventral axis formation (Science 1997, Nature 2002), neurite extension (Science 2005), exocrine secretion (Science 2005), learning and memory (Nature 2000, Nature Neurosci 2015), behavior (Nature 1996), apoptosis (Cell 2005, Neuron 2010, eLife 2016), and human genetic diseases, such as anhydrosis (J Clin Invest 2014) and spinocerebellar ataxia 29 (PNAS 2018). We also discovered a pseudo-ligand for IP₃R, IRBIT (IP₃R binding protein released with IP₃) (Mol Cell 2006), which works as an assumed third messenger to regulate acid-base balance by activating Na⁺/HCO₃^- co-trasnporter 1, Na⁺/H⁺ exchanger, and CFTR channel. Based on these findings, our lab will conduct cutting-edge researches under collaborative and worldwide scientific environments with fully innovative equipment and facilities at ShanghaiTech University and another Mikoshiba lab at Toho University in Japan.

OUR PROJECTS

We are interested in the role and mechanism of cell signaling focusing especially on the transduction of the Ca²⁺ signaling. We are studying mainly four core projects as follows.

1.Calcium Signaling in Brain

Calcium signaling in the brain is essential to maintain a normal brain structure and function. We shall study molecular mechanisms by which the IP₃ receptor control neuronal morphology and function. Glial cells surround neurons to modulate their functions, so glial IP₃ receptors will be also targets for our study.

2.Calcium Signaling in Differentiation

We discovered IP₃ receptor is involved in cell differentiation and development. We shall study how IP₃R is involved in cell fate determination by detailed analysis of local Ca²⁺ signaling mediated by IP₃ receptors at cellular microdomains.

3.IP₃ receptor Structure and Function

Recent studies have demonstrated atomic structures of IP₃ receptors and ryanodine receptors, suggesting a shared gating mechanism. However, we have never known how IP₃ and Ca²⁺ bind to open the channel. We shall study the gating mechanism controlled by IP₃ and Ca²⁺.

4.IRBIT Function and Mechanism

IRBIT is an IP₃ receptor binding protein released in the presence of IP₃, which is discovered and named in the Mikoshiba lab.  IRBIT regulates Ca²⁺ signaling, the intracellular pH homeostasis, and ribonucleotide reductase which controls tumor growth. We shall study molecular mechanism of how IRBIT controls these cellular signaling.

Main Publications     Katsuhiko Mikoshiba： 

total citation 73,237. h index 128 i10 index 678 

1.       Mikoshiba, K. et al.  RNA-dependent RNA synthesis in rat brain. Nature249 445-448 (1974)

2.       Hozumi, N. et al.   Poly (U) polymerase in rat brain. Nature256 337-339 (1975)

3.       Mikoshiba, K. et al. Oligodendrocyte abnormalities in shiverer mouse mutant are determined in primary chimaeras. Nature: 299 357-359  (1982)

4.       Furuichi, T, et al. Primary structure and   functional expression of the inositol 1,4,5-trisphosphate-binding protein   P400. Nature 342(6245):32-8. (1989)

5.       Miyawaki, A. et al. Expressed cerebellar-type inositol 1,4,5-trisphosphate receptor, P400 has calcium release activity in a fibroblast L cell line. Neuron5 11-18 (l990)

6.       Miyawaki, A. et al.  Structure-function relationships of the mouse inositol 1,4,5-trisphosphate receptor. Proc. Natl. Acad. Sci.  88 4911-15 (1991)

7.       Mori,Y. et al.  Primary structure and functional expression from complementary DNA of a brain calcium channel. Nature 350 398-402 (1991)

8.       Turnley, A.M.et al. Dysmyelination in transgenic m. ice resulting from expression of class I histocompatibility molecules in oligodendrocytes. Nature 353 566-69 (1991)

9.       Mikoshiba, K, Okano H, Tamura T.A, Ikenaka K Structure and Function of Myelin Protein Genes.  AnnualReview of Neuroscience Vol. 14:201-217 (1991) 

10.   Kuwajima, G. et al,  Two types of ryanodine receptors in mouse brain: Skeletal muscle type exclusively in Purkinje cells and cardiac muscle type in various neurons. Neuron9 1133-42 (1992)

11.   Fujita, Y. et al.  Primary structure and functional expression of the w-conotoxin-sensitive N-type calcium channel from rabbit brain. Neuron10 585-598 (1993)

12.   Miyazaki, S. et al. Block of Ca²⁺ wave   and Ca²⁺ oscillation by antibody to the inositol   1,4,5-trisphosphate receptor in fertilized hamster eggs.  Science 257:251-5.   (1992)

13.   Kume, S. et al.  The Xenopus IP3 receptor : structure, functiion, and localization in oocytes and eggs. Cell73 555-570 (1993)

14.   Kawasaki, M. et al. Cloning and expression of a protein kinase C-regulated chloride channel abundantly expressed in rat brain neuronal cells.Neuron12 597-604 (1994)

15.   Kagawa, T. et al.   Glial cell degeneration and hypomyelination caused by overexpression of myelin proteolipid protein gene. Neuron13 427-442 (1994)

16.   Llinás, R. et al.   The inositol high-polyphosphate series blocks synaptic transmission by preventing vesicular fusion: A squid giant synapse study. Proc. Natl. Acad. Sci.  91 12990-93 (1994)

17.   Ogawa, M. et al. The reeler gene-associated antigen on Cajal-Retzius neurons is a crucial molecule for laminar organization of cortical neurons. Neuron14 899-912 (1995)

18.   Fukuda, M. et al,  Role of the C2B domain of synaptotagmin in vesicular release and recycling as determined by specific antibody injection into the squid giant synapse preterminal. Proc. Natl. Acad. Sci. 92 10708-712 (1995)

19.   Mikoshiba, K. et al.  Role of the C2A domain of synaptotagmin in transmitter release as determined by specific antibody injection into the squid giant synapse preterminal. Proc. Natl. Acad. Sci.92 10703-707 (1995)

20.   Matsumoto M. et al.  Ataxia and epileptic seizures   in mice lacking type 1 inositol 1,4,5-trisphosphate receptor. Nature 379(6561):168-71.   (1996)

21.   Nakajima, K. et al.   Distruption ofhippocampal development in vivo by CR-50 mAb against reelin. Proc. Natl. Acad. Sci.  94 8196-201 (1997)

22.   Nakata, K. et al,   Xenopus Zic3, a primary regulator both in neural and neural crest development. Proc. Natl. Acad. Sci.94 11980-85 (1997)

23.   Kume S. et al. Role of inositol   1,4,5-trisphosphate receptor in ventral signaling in Xenopus embryos. Science   278(5345):1940-3. (1997)

24.   Del Rio J.A.et al. A role for Cajal-Retzius cells and reelin in the development of hippocampal connections. Nature 385 70-74 (1997)

25.   Sheldon, M. et al.    Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice. Nature389 730-733 (1997)

26.   Umemori H. et al.  Activation of the G protein Gq/11 through tyrosine phosphorylation of the a subunit. Science 276 1878-1882 (1997)

27.   Takei K et al. Regulation of nerve growth   mediated by inositol 1,4,5-trisphosphate receptors in growth cones. Science   282:1705-1708. (1998)

28.   Zhao, H. et al. Functional expression of a mammalian odorant receptor. Science279 237-242 (1998)

29.   Boulay, G. et al.    Modulation of Ca2+ entry by polypeptides of the inositol 1,4,5-trisphosphate receptor (IP3R) that bind transient receptor potential (TRP): evidence for roles of TRP and IP3R in store depletion activated Ca2+ entry. Proc. Natl. Acad. Sci.96 14955-60 (1999)

30.   Futatsugi, A. et al.    Facilitation of NMDA receptor-independent LTP and spatial learning in mutant mice lacking Ryanodine receptor type 3. Neuron24 701-713 (1999)

31.   Ma, H.T. et al. Requirement of the inositol trisphosphate receptor for activation of store-operated Ca2+ channels. Science287 1647-1651 (2000)

32.   Nishiyama, M. et al. Calcium stores regulate the polarity and input specificity of synaptic modification.  Nature 408  584-588  (2000)

33.   Nagai, T.  et al.  Zic2 regulates the kinetics of neurulation. Proc. Natl. Acad. Sci.97 1618-1623 (2000)

34.   Utsunomiya-Tate, N. et al,   Reelin molecules assemble together to form a large protein complex, which is inhibited by the function-blocking CR-50 antibody. Proc. Natl. Acad. Sci. USA 97 9729-9734 (2000)

35.   Fukami, K. et al. Requirement of phospholipase Cδ4 for the Zona pellucida-induced acrosome reaction.  Science  292  920-923  (2001)

36.   Nagai T. et al.  A variant of yellow fluorescent   protein with fast and efficient maturation for cell-biological   applications.  Nature Biotechnology  20 87-90 (2002)

37.   Saneyoshi T. et al.  The Wnt/calcium pathway   activates NF-AT and promotes ventral cell fate in Xenopus embryos.  Nature   417:295-299. (2002)

38.   Herrera, E. et al.   Zic2 patterns binocular vision by specifying the uncrossed retinal projection.   Cell  114 545-557 (2003)

39.   Hirasawa, M. et al. Perinatal abrogation of Cdk5 expression in brain results in neuronal migration defects. Proc. Natl. Acad. Sci.101(16):6249-6254 (2004)

40.   Bosanac, I. et al. Crystal structure of the ligand binding suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor Molecular Cell17:193-203 (2005)

41.   We,i F-Y. et al.  Cdk5-dependent regulation of glucouse-stimulates insulin secretion Nature Medicine11(10):1104-1108 (2005)

42.   Higo, T. et al. Subtype-specific and ER   lumenal environment-dependent regulation of inositol 1,4,5-trisphosphate  receptor type 1 by ERp44.   Cell 120(1):85-98. (2005)

43.   Futatsugi A. et al. IP3 receptor types 2 and 3   mediate exocrine secretion underlying energy metabolism.   Science   309(5744):2232-4. (2005)

44.   Shirakabe, K. et al.   IRBIT specifically binds to and activates pancreas-type Na+/HCO3- cotransporter 1, pNBC1. Proc. Natl. Acad. Sci.103(25):9542-9547 (2006)

45.   Kuroda, Y. et al.   Osteoblasts induce Ca2+ oscillation-independent NFATc1 activation during osteoclastogenesis Proc. Natl. Acad. Sci. 105(25):8643-8648 (2008)

46.   Higazi, DR. et al.  Endothelin-1-stimulated InsP3-induced Ca2+ release is a nexus for hypertrophic signaling in cardiac myocytes. Molecular Cell33(4): 472-82 (2009)

47.   Bannai, H. et al.  Activity-dependent tuning of inhibitory neurotransmission based on GABAAR diffusion dynamics. Neuron 62(5):670-82. (2009)

48.   Ando, H. et al.  IRBIT suppresses IP3 receptor   activity by competing with IP3 for the common binding site on the IP3   receptor.   Molecular Cell 22(6):795-806. (2006)

49.   Higo, T. et al.  Mechanism of ER   stress-induced brain damage by IP₃ receptor. Neuron  68(5):865-78.   (2010)

50.   Horikawa, K. et al. Spontaneous network   activity visualized by ultrasensitive Ca²⁺indicators, yellow   Cameleon-Nano. Nature Methods 7:729-732. (2010)

51.   Maul-Pavicic A. et al . ORAI1-mediated calcium influx is required for human cytotoxic lymphocyte degranulation and target cell lysis. Proc Natl Acad Sci.108(8): 3324-9 (2011)

52.   Shinohara, T. et al.  Mechanistic basis of bell-shaped dependence of inositol 1,4,5-trisphosphate receptor gating on cytosolic calcium. Proc Natl Acad Sci.108(37): 15486-91 (2011)

53.   Klar, J. et al. InsP₃R2 mutations cause  anhidrosis in humans   and hypohidrosis in mice.   J. Clinical Investigation    124(11): 4773-80 (2014)

54.   Hamada, K. et al. Aberrant calcium signaling by transglutaminase-mediated posttranslational modification of inositol 1,4,5-trisphosphate receptors. Proc Natl Acad Sci.111(38): E3966-75 (2014)

55.   Tsuboi, D. et al.  Disrupted-in-schizophrenia 1 regulates   transport of ITPR1 mRNA for synaptic plasticity. Nature   Neuroscience 18(5): 698-707. (2015)

56.   Bannai, H. et al.   Bidirectional control of synaptic      GABAAR clustering by glutamate and calcium Cell Reports 13:1-3 (2015)

57.   Ushioda, R. et al.   Redox-assisted regulation of Ca2+ homeostasis in the endoplasmic reticulum by disulfide reductase ERdj5. Proc Natl Acad Sci.113(41): E6055-E6063. (2016)

58.   Hisatsune, C. et al. ERp44 Exerts redox-dependent   control of blood pressure at the ER.    Molecular   Cell. 58(6): 1015-27.   (2015)

59.   Monai, H. et al. Calcium imaging reveals glial   involvement in transcranial direct current stimulation-induced plasticity in   mouse brain. Nature Communications doi: 10.1038/ncomms1 1100   (2016)

60.   Bonneau, B. et al. IRBIT controls apoptosis by interacting with the Bcl-2   homolog, Bcl2l10, and by promoting ER-mitochondria contact.   eLife   DOI10.7554/eLife19896 (2016)

61.   Kawaai, K.  Splicing variation of Long-IRBIT determines the target selectivity of IRBIT family proteins. Proc Natl Acad Sci.114(15): 3921-3926. (2017)

62.   Tobe, BTD. et al.  Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis. Proc Natl Acad Sci.114(22):E4462-E4471. (2017)

63.   Sugawara, T. et al.  Regulation of spinogenesis in mature Purkinje cells via mGluR/PKC -mediated phosphorylation of CaMKIIβ. Proc Natl Acad Sci.114(26): E5256-E5265. (2017)

64.   Nakayama, K. et al.   RNG105/caprin1, an RNA granule protein for dendritic mRNA localization, is essential for long-term memory formatione  eLife DOI:https://doi.org/10.7554/eLife.29677.001 (2017)

65.   Hamada, K. et al. IP₃-mediated gating mechanism of the IP₃ receptor revealed by mutagenesis and X-ray crystallography. Proc Natl Acad Sci. 114(18): 4661-4666. (2017)

66.   Ando, H. et al.  Aberrant IP3 receptor activities revealed by comprehensive analysis of pathological mutations causing spinocerebellar ataxia 29. Proc Natl Acad Sci.115 (48) 12259-12264 (2018)

67.   Nakayama, K. et al.     RNG105/caprin1, an RNA granule protein for dendritic mRNA localization, is essential for long-term memory formatione    eLife   DOI:https://doi.org/10.7554/eLife.29677.001  (2018)

68.   Bartok, A. et al. IP3 receptor isoforms differently regulate ER-mitochondrial contacts and local calcium transfer.Nature Communications 10(1) 3726  (2019)

69.   Shiratori-Hayashi, M. et al. Astrocytic STAT3 activation and chronic itch require IP3R1/TRPC- Ca2+ signals in mice, Journal of Allergy and Clinical Immunology (2020), doi: https:// doi.org/10.1016/j.jaci.2020.06.039. (2020)

70.   Hamada K. Mikoshiba K. IP3 receptor plasticity underlying diverse functions.   Annual Review of Physiology. annurev-physiol-021119-03443382  pp. 151–176 (2020)  

71.   Kabayama, H, An ultra-stable cytoplasmic antibody engineered for in vivo applications. Nature Communications (2020)11:336 | https://doi.org/10.1038/ s41467-019-13654-9  (2020)

72.   Arizono, M. et al.  Structural basis of astrocytic Ca²⁺ signals at tripartite synapses. Nature Communications| (2020)11:1906 | https://doi.org/10.1038/s41467-020-15648-4 | www.nature.com/ naturecommunications   (2020)

73.   Kohro, Y. et al.  Spinal astrocytes in superficial laminae gate brainstem descending control of mechanosensory  hypersensitivity   Nature Neuroscience.  NN-A63885B  (2020)