Katsuhiko Mikoshiba

Studies on the development, growth differentiation, of the nervous system.

Brain plays an important role for learning and memory and behavior, and it is composed of various types of cells such as neurons and glial cells. My lab has been intensively working on the function of each neuron and glia. To understand deeply the brain function, we introduced mutant mice which show abnormal behavior and abnormal morphogenesis.  We studied the mutants at the level of morphology, molecules and behavior.  We worked on the high molecular weight P₄₀₀ protein greatly decreased in the cerebellum of Purkinje cell-degeneration mutant mice (Dev. Neurosci 1979), and discovered that P₄₀₀ is the IP₃ receptor (IP₃R) which plays an essential role in cell signaling.  We cloned the whole cDNA sequence (Nature 1989) showing that it is the IP₃R essential for Ca²⁺ release.

We found IP₃R is important in producing Ca²⁺ oscillation (Science 1998) essential for fertilization (Science 1992), growth cone extension (Science Sig 2009), and behavior (Nature 1996).  Biochemical and X ray crystallographic analysis (Nature 2002, Mol. Cell 2005, PNAS 2017, Annual Rev. Physiol 2020) showed biochemical property and the gating mechanism of IP₃R.

We found the chaperons (GRP78 (Neuron 2010) and ERp44 (Cell 2005, 2015))bind to IP₃R and these chaperons work for protecting the brain from brain damage.  We discovered a human mutation of IP₃R2 gene that results in anhidrosis (inablility to sweat) (J.Clinical Invest.2014).  IP₃R2 and 3 double KO mice show abnormal exocrine function with symptoms of dry mouth and dry eye similar to that of Sjögren's syndrome (Science 2005), indicating that IP₃Rs are indeed involved in exocrine secretion.  We also found that IP₃R is involved in heart function (Circulation Res. 2010a,b) and cardiogenesis by producing double KO (IP₃R1, 2) and double KO (IP₃R1, 3) mice (PLoS One 2010)(J. Mol.Cellular Cardiology 2011).  IP₃Rs associate with many functional molecules and work as a signaling hub offering a platform in association with the many functional molecules and plays complex functions.

In addition, we discovered a new molecule which is released from IP₃R in the presence of IP₃ and we named it IRBIT (IP₃receptor binding protein released with inositol 1,4,5-trisphosphate) as a novel pseudo-ligand of the IP₃Rs (JBC 2003, Mol. Cell 2006).  IRBIT activates the Na⁺_/HCO₃⁻ cotransporter 1 (PNAS 2006) and CFTR (Cl^- transporter) (J. Clinical Invest. 2009, 2010) andNa⁺H⁺ exchanger (JBC 2013) thereby regulating acid-base balance  (PNAS 2006). IRBIT also regulates the CaMKIIα kinase activity (PNAS 2015) which is highly involved in learning and memory in the brain. It was reported that IRBIT works for tumor-suppressor.  It is surprising to know that IRBIT is working as another signaling hub like IP₃R.