Laboratory for Developmental Neurobiology

Katsuhiko MIKOSHIBA, M.D., Ph.D.
Laboratory Head

Main Publications at RIKEN

Research Areas

The brain is composed of billions of neurons and glial cells, and their intimate communications are very important for the higher brain function. 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, we have been focusing on the physiological role of IP₃Rs that affect intracellular Ca²⁺ dynamics by releasing Ca²⁺ from the intracellular Ca²⁺ store, and revealed the crucial role of IP₃Rs in various physiological phenomena including dorso-ventral axis formation in early development, synaptic plasticity, dendrite formation of neurons, fertilization, and endocrine secretion. Using genetic mutant mice, our groups are going to further study the role of IP₃Rs in the higher brain function (memory, emotion, locomotion) and brain diseases (schizophrenia, epilepsy). In addition, we are also interested in the molecular mechanism how the complex spatio-temporal patterns of Ca²⁺ dynamics e.g. Ca²⁺ waves and Ca²⁺ oscillations, are generated in various types of cells. For the purpose, we are aiming to clarify the gating mechanism of IP₃R, the spatio-temporal dynamics of both cytosolic IP₃ and Ca²⁺, and the regulatory mechanism of Ca²⁺ puffs that are the elementary Ca²⁺ events. We have also interests in the regulation of IP₃R by binding proteins. Recently, we found a novel IP₃R-binding protein, named IRBIT, which carries MSR in the N-terminal region. Our hypothesis is that the phosphorylation patterns in MSR direct the IRBIT to mimic phosphoinositides (PIs) such as PI, PI(4,5)P2, PI(3,4,5)P3, or inositol poly-phosphates (IPPs) such as IP₃, IP4, and that IRBIT can spatio-temporaly modulate the PIs /IPPs-mediated signaling pathway by changing the expression levels, phosphorylation status, and subcellular distribution. In fact, some phosphorylated forms of IRBIT mimic IP₃ and set the IP₃ sensitivity of IP₃R. Now, we are eagerly trying to identify protein kianses and phosphatases which regulate IRBIT phosphorylation status, and also trying to identify other IRBIT binding molecules. To achieve these purposes, we are using physico-chemical techniques such as electrophysiology, fluorescence imaging, and single molecule imaging, in addition to molecular, cellular and structure biology.

Intracellular signal transduction and calcium signaling

Research Subjects

Analysis of the role of IP₃Rs in the brain function and disease using genetic mutant mice.
Simultaneous imaging of [Ca²⁺] and [IP₃] in living cells using FRET-based IP₃ sensors and fluorescent Ca²⁺ indicators. Detecting and characterising local Ca²⁺ signalling patterns medeated by IP₃Rs.
Gating mechanism of IP₃R and channel regulation by IP₃R-modulators
Comprehensive understanding of Phosphoinositides/Inositol poly-phosphates/Calcium signaling. - IP₃R and its binding proteins, as centers of the signaling

Selected Publications

Saneyoshi, T., Kume, S., Amasaki, Y., and Mikoshiba, K.:
"The Wnt/Calcium pathway activates NF-AT and promotes ventral cell fate in Xenopus embryos."
Nature, 417, 295-299 (2002).
Kawaai, K., Hisatsune, C., Kuroda, Y., Mizutani, A., Tashiro, T., and Mikoshiba, K.:
"80K-H interacts with inositol 1,4,5-trisphosphate receptors and regulates IP3-induced calcium release activity."
J Biol Chem. 284(1):372-80 (2009)
Kuroda, Y., Hisatsune, C., Nakamura, T., Matsuo, K., and Mikoshiba, K.:
"Osteoblasts induce Ca2+ oscillation-independent NFATc1 activation during osteoclastogenesis."
Proc. Natl. Acad. Sci. 105(25):8643-8648 (2008)
Mizutani, A., Kuroda, Y., Futatsugi, A., Furuichi, T., and Mikoshiba, K.:
"Phosphorylation of Homer3 by Calcium/Calmodulin-Dependent Kinase II Regulates a Coupling State of Its TargetMolecules in Purkinje Cells."
J. Neurosci. 28(20):5369 –5382 (2008)
Ohshima, T., Hirosawa, M., Tabata, H., Mutoh, T., Adachi, T., Suzuki, H., Saruta, K., Iwasato, T., Itohara, S., Hashimoto, M., Nakajima, K., Ogawa, M., Kulkaruni, A.B., and Mikoshiba, K.:
"Cdk5 is required for multipolar-tobipolar transition during radial neuronal migration and proper dendrite development of pyramidal neurons in the cerebral cortex."
Development,１３４, 2273-82（2007)
Shirakabe, K., Priori, G., Yamada, H., Ando, H., Horita, S., Fujita, T., Fujimoto, I., Mizutani, A., Seki, G., and Mikoshiba, K.:
"IRBIT.,an inositol 1,4,5-trisphosphate receptor-binding protein.,specifically binds to and activates pancreas-type Na+/HCO3- cotransporter 1(pNBC1)."
Proceedings of the National Academy of Sciences of the United States of America, 103, 9542-9547 (2006).
Ando, H., Mizutani, A., Kiefer, H., Tsuzurugi, D., Michikawa, T., and Mikoshiba, K.:
"IRBIT suppresses IP3 receptor activity by competing with IP3 for the common binding site on the IP3 receptor."
Molecular Cell, 22, 795-806 (2006).
Matsu-ura, T., Michikawa, T., Inoue, T., Miyawaki, A., Yoshida, M., and Mikoshiba K.:
"Cytosolic inositol 1,4,5-trisphosphate dynamics during intracellular calcium oscillations in living cells."
The Journal of Cell Biology, 1735, 755-765 (2006).
Futatsugi, A., Nakamura, T., Yamada, MK., Ebisui, E., Nakamura, K., Uchida, K., Kitaguchi, T., Takahashi-Iwanaga, H., Noda, T., Aruga, J., and Mikoshiba, K.:
"IP3 receptor types 2 and 3 mediate exocrine secretion underlying energy metabolism."
Science, 309, 2232-2234 (2005).
Higo, T., Hattori, M., Nakamura, T., Natsume, T., Michikawa, T., and Mikoshiba, K.:
"Subtype-specific and ER lumenal environment-dependent regulation of inositol 1,4,5-trisphosphate receptor type 1 by ERp44."
Cell, 120, 85-98 (2005).

Main Publications at RIKEN

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