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Séminaire impromptu - Katsuhiko Mikoshiba"Role of IP3 receptor/calcium channel in neuronal functions and diseases"

Abstract :

Une invitation de Valentin Nagerl

Research Area

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.

Selected publications

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)

Kuroda Y, Hisatsune C, Nakamura T, Matsuo K, and Mikoshiba K: "Osteoblasts induce Ca2+ oscillation-independent NFATc1 activation during osteoclastogenesis.", Proc Natl Acad Sci U S A, 105(25), 8643-8 (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 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)

Valentin Nägerl de l'IINS

Katsuhiko Mikoshiba

Riken Brain Science Institute
M.D., Ph.D.
Our laboratory is focusing on the role of calcium signaling in neurobiological activities and diseases.
Developmental Neurobiology
Senior Team Leader