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Involvement of the Calcium-Calmodulin System in the Cerebellar IP3 Receptor Adjustment Functions

Laboratory for Developmental Neurobiology
Dr. Katsuhiko Mikoshiba, Head of the Lab. for Developmental Neurobiology, Dr. Maki Yamada, Special Postdoctral Researcher and Dr. Teiichi Furuichi, Head of the Lab. for Molecular Neurogenesis et al. have explained for the first time how the calcium-calmodulin system is involved in the adjustment functions of the cerebellar IP3 receptor.

Inositol, 1,4,5-trisphosphate (IP3) is produced by stimulating cells caused by neurotransmitters, neurotrophic factors, etc. IP3 acts upon the IP3 receptor (IP3 activating Ca2+ channel) in the intracellular Ca2+ store to induce the release of Ca2+ into the cytoplasm. It is deeply involved in the neural function (synaptic plasticity, neurite extension, etc.) and neural diseases (epileptic seizure, neuronal cell death, etc.). The activation of the IP3 receptor causes not only a transient increase in cytoplasmic Ca2+ but also results in repeated positive and negative regulation feedback by the released Ca2+, (diphasic control at low Ca2+ and high Ca2+, with a peak at approximately 0.5 M). This results in spatial-temporal Ca2+ dynamics such as in Ca2+ waves and Ca2+ oscillations. However, much remains unknown as to these mechanisms at the molecular level.

In the recent research, we have reconstructed parified type 1 IP3 receptors into an artificial planar lipid bilayers to examine at single channel-decording levels, and have clarified that in the absence of calmodulin the Ca2+ basically acts positively on the IP3 receptors but in the presence of calmodulin negatively in the high Ca2+ domain. In other words, we have demonstrated that the high Ca2+ sensor of the IP3 receptor is the calmodulin, which exists abundantly in the brain and that the Ca2+ bound calmodulin probably inactivates the IP3 receptor by directly linking with the IP3 receptor.

These results have been achieved following joint research undertaken together with the Institute of Medical Science, University of Tokyo, the Tokyo Medical and Dental College and the Japan Science and Technology Corporation (JST).

Michikawa, T., Hirota, J., Kawano, S., Hiraoka, M., Yamada, M., Furuichi, T., Mikoshiba, K.
Calmodulin Mediates Calcium-Dependent Inactivation of the Cerebellar Type 1 Inositol 1,4,5-Trisphosphate Receptor
Neuron, Vol. 23, pp. 1-10, August (1999)

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