| Co-Investigator(Kenkyū-buntansha) |
WAKAMORI Minoru National Institute for Physiological Sciences, Research Associate, 生理学研究所, 助手 (50222401)
NAKAI Junichi National Institute for Physiological Sciences, esearch Associate, 生理学研究所, 助手 (80237198)
MORI Yasuo National Institute for Physiological Sciences, Associate Professor, 生理学研究所, 助教授 (80212265)
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| Research Abstract |
We investigated dynamic aspect of local ionic signaling en central neurons, by comparing wild-type and mutant functional molecules or mouse strains. More precisely, we studied molecular biological and electrophysilogical analyses of voltage-gated calcium channels and receptor-activated calcium permeable cation channels. We clarified some steps of the pathogenic mechanism how the calcium channel mutations lead to cerebellar ataxia. Also we showed that receptor-activated calcium permeable channels are expressed in a wide range of tissues including brain, and are critically involved in various aspects of cell regulation.
To uncover the pathogenic mechanism of human spinocerebellar ataxia type 6, which has been shown to be associated with CAG nucleotide repeat extension in the P/Q-type calcium channel, we analyzed functional properties of the calcium channel with the extension in a recombinant expression system, to obtain the negative shift of voltage-dependent inactivation. This change is
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consistent with the idea that reduced calcium influx can be a cause of the cerebellar neuronal disorder.
We identified the mutation in the calcium channel α1A gene of the mutant ataxic mouse rolling nagoya. The mutation was located in the voltage sensing region. In fact, the calcium channel was shown to have a reduced voltage sensitivity in addition to reduced current amplitude. This study showed how a single mutation leads to abnormal development and function of the neuronal circuit.
The TRP channel is a representative of receptor-activated channels. We conducted molecular analyses of the members of the TRP channel family. The functional properties of TRP channels are characterized using recombinant expression systems. In particular, TRP7, which is constitutively activated without external stimulation, was shown to be functionally similar to the channel previously identified as a calcium permeable non-selective cation channel. The members of TRP channel family may contribute to sustained depolarization of neurons when then receive repetitive stimulations. Less
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