Senior Team Leader
IP3 receptor, Calcium signaling
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), 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(Cell 1993, 1996 J. Cell Biol., Nature 2002, Science 1997), synaptic plasticity(J. Neurosci. 2011, Nature 2000, Learning & Memory 2000), neural circuit formation(Science 1998, Science Signaling 2009, J. Neurosci. 2011), dendrite formation of neurons(J. Neurosci. 2006), fertilization (Science 1992), 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 disease, Alzheimer disease and other ataxic diseases). 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(PNAS 2011, J. Biol. Chem. 2007) the spatio-temporal dynamics of both cytosolic IP3 and Ca2+(J. Cell Biol. 2006), and the regulatory mechanism of Ca2+ puffs(J. Biol. Chem. 2012) that are the elementary Ca2+ events. We have also interests in the regulation of IP3R by binding proteins.
During the search for molecules biochemically associated with IP3R, 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).
We have demonstrated that subcompartments of the ER called vesicular ERs can be rapidly transported along neuronal dendrites. The transport of vesicular ERs is bi-directional and requires microtubules and kinesin. The vesicular ERs can take up and release Ca2+ and may therefore contribute to the spatial regulation of intracellular Ca2+ signaling (J.Cell Sci. 2004b). mRNA granules containing IP3Rs also move along microtubules(J. Biol. Chem. 2004).
We have determined the crystal structure of the IP3 binding core domain at a resolution of 2.2Å (Nature 2002), and of the suppressor domain at a resolution of 1.8Å(Molecular Cell 2005). Negative staining of the purified receptor revealed dynamic reversible structural changes in the presence and absence of Ca2+, suggesting that the IP3R molecule is an allosteric protein regulated by Ca2+(J. Biol. Chem. 2002, 2003).
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). IP3R associates with more than 20 functional molecules and functions as a signaling hub that is a good fit for the 3-dimensional balloon-like structure containing a large cavity inside with many pores on the surface that was identified by cryoEM (J. Mol. Biol. 2004).
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
Arizono M, Bannai H, Nakamura K, Niwa F, Enomoto M, Matsu-Ura T, Miyamoto A, Sherwood MW, Nakamura T, and Mikoshiba K: "Receptor-selective diffusion barrier enhances sensitivity of astrocytic processes to metabotropic glutamate receptor stimulation.", Sci Signal, 5(218), ra27 (2012)
Higo T, Hamada K, Hisatsune C, Nukina N, Hashikawa T, Hattori M, Nakamura T, and Mikoshiba K: "Mechanism of ER stress-induced brain damage by IP(3) receptor.", Neuron, 68(5), 865-78 (2010)
Horikawa K, Yamada Y, Matsuda T, Kobayashi K, Hashimoto M, Matsu-ura T, Miyawaki A, Michikawa T, Mikoshiba K, and Nagai T: "Spontaneous network activity visualized by ultrasensitive Ca(2+) indicators, yellow Cameleon-Nano.", Nat Methods, 7(9), 729-32 (2010)
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 target molecules in Purkinje cells.", J Neurosci, 28(20), 5369-82 (2008)
Ohshima T, Hirasawa M, Tabata H, Mutoh T, Adachi T, Suzuki H, Saruta K, Iwasato T, Itohara S, Hashimoto M, Nakajima K, Ogawa M, Kulkarni AB, and Mikoshiba K: "Cdk5 is required for multipolar-to-bipolar transition during radial neuronal migration and proper dendrite development of pyramidal neurons in the cerebral cortex.", Development, 134(12), 2273-82 (2007)
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.", J Cell Biol, 173(5), 755-65 (2006)
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).", Proc Natl Acad Sci U S A, 103(25), 9542-7 (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.", Mol Cell, 22(6), 795-806 (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(5744), 2232-4 (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(1), 85-98 (2005)
- Dec. 9, 2010 New study uncovers how cellular stress causes brain damage Katsuhiko MIKOSHIBA, M.D., Ph.D., Developmental Neurobiology
- Jun. 12, 2009 Cell to cell efficiency in the brain Katsuhiko MIKOSHIBA, M.D., Ph.D., Developmental Neurobiology, Hiroko BANNAI, Ph.D., Developmental Neurobiology
- May. 8, 2007 Layering and positioning neurons The Developmental Neurology Team has discovered an enzyme that plays a critical role in the formation of the layered structure of the cerebral cortex. Toshio OSHIMA, M.D., Ph.D., The Developmental Neurology
- Oct. 18, 2006 Insights into brain architecture Katsuhiko MIKOSHIBA, M.D., Ph.D., Developmental Neurobiology
- Jun. 23, 2006 Molecular mimic sets the tone for calcium release Katsuhiko MIKOSHIBA, M.D., Ph.D., Developmental Neurobiology
- Jun. 13, 2006 More responsibilities for a busy pathway Katsuhiko MIKOSHIBA, M.D., Ph.D., Developmental Neurobiology
- Jun. 5, 2006 New mechanism responsible for the generation of calcium oscillations: Dynamics associated with slow intra-cellular accumulation of inositol trisphosphate Katsuhiko MIKOSHIBA, M.D., Ph.D., Developmental Neurobiology
- Sep. 30, 2005 Calcium release through IP3 receptors(type 2 and 3) is essential for exocrine function Katsuhiko MIKOSHIBA, M.D., Ph.D., Developmental Neurobiology
- Jan. 14, 2005 Discovery of a Redox Sensor Protein Capable of Recognizing the Oxidation Stress of Organisms and Elucidation of Part of the Stress Control Mechanism Katsuhiko MIKOSHIBA, M.D., Ph.D., Developmental Neurobiology