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 (1st 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 1st 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)
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