Research Director: Dr. Katsuhiko Mikoshiba
(Professor, The Institute of Medical Science, The University of Tokyo / Group Director, Brain Science institute, RIKEN)
Research Term: 1995-2000

The Mikoshiba calciosignal net project sought ways to better understand the roles of calcium and IP3 in cells as well as their mechanisms in order to establish a more complete and accurate view of cell biochemistry, which should eventually lead to useful pharmacological products and cures of various diseases related to malfunctioning cells.

Research Results

Calcium wave formation at the cleavage furrows: The intracellular free calcium in cleavage-stage Xenopus embryos was studied. Cleavage formation was followed by calcium transients that localized to each stage of cleavage furrows and propagated along the furrows as calcium waves, at least until the blastula stage. The velocity of calcium waves implied an intracellular calcium-releasing activity specifically associated with cleavage furrows. Experiments suggest that IP₃ receptor-mediated calcium mobilization plays an essential role in this process.

Dorso-ventral axis formation: Evidence has been obtained that blockage of IP₃-induced calcium release in the ventral part of the embryo leads to the conversion of the ventral mesoderm to the dorsal mesoderm, thereby generating ectopic dorsal axes. This finding suggests a role for the IP₃/calcium signaling pathway as a ventralizing signal in addition to the already known pathway through glycogen synthase kinase 3b.

IP₃R1 essential for proper brain function: It has been found that most IP₃R1-deficient mice generated by gene targeting die in utero, and born animals have severe ataxia and tonic or tonic-clonic seizures and die by the weaning period. Electroencephalograms have shown that they suffer from epilepsy, indicating that IP₃R1 is essential for proper brain function. It was further found that that the IP₃-receptor-defficient knocked-out mice could be used as valuable model animals in developing drugs for epilepsy and cerebellar ataxia.

Development of the micro-CALI process: It has been shown using micro-CALI that IP₃ receptors could be inactivated. This procedure provided important clues concerning the outgrowth of the neuronal axon. Experiments suggest that calcium-ion release mediated by the IP₃ receptor is deeply involved in neuronal network formation during development and during the learning process.

IP₃ receptor in cerebellar plasticity: Purkinje neurons injected with the IP₃ receptor antibody and that from the IP₃ receptor deficient mice showed a blockage of LTD, suggesting the importance of the IP₃ receptor in cerebellar plasticity.

Potency of IP₃ induced calcium signaling in cell-shape change: The injection of IP₃ into fertilized Xenopus eggs induces a transient calcium increase, and a concomitant cell shape change, showing both contraction and swelling, starting at the injection site accompanying rearrangement of cytoskeletal proteins. The result obtained in the project concludes that calcium release from internal store though IP₃ receptor plays a crucial role in cell function.

Xenopus embryo injeted with a function-blocking antiboby against IP₃ receptor

Role for the Ca²⁺ release in the cell signaling