Dynamic analysis of subcellular ionic signalling in neurons

我们通过比较野生型和突变型功能分子或小鼠品系，研究了中枢神经元局部离子信号的动态方面。更准确地说，我们研究了电压门控钙通道和受体激活的钙渗透性阳离子通道的分子生物学和电生理学分析。阐明了钙通道突变导致小脑性共济失调的发病机制。我们还发现，受体激活的钙离子通道在包括脑在内的广泛组织中表达，并且在细胞调节的各个方面都有重要作用。为了揭示人类脊髓小脑共济失调6型的致病机制，该机制已被证明与P/Q型钙离子通道中的CAG核苷酸重复序列延伸有关，我们在重组表达系统中分析了具有延伸的钙通道的功能特性，以获得电压依赖性失活的负移。这种变化是 ...更多信息 这与钙内流减少可能是小脑神经元紊乱的原因这一观点相一致。我们鉴定了突变型共济失调小鼠rolling名古屋的钙通道α1A基因突变。突变位于电压敏感区。事实上，钙通道显示出除了降低的电流幅度之外还具有降低的电压敏感性。该研究揭示了单个突变如何导致神经回路的发育和功能异常。TRP通道是受体激活通道的代表。我们对TRP通道家族的成员进行了分子分析。TRP通道的功能特性的特点是使用重组表达系统。特别是，TRP 7，这是组成性激活无外部刺激，显示功能类似于先前确定为钙渗透性非选择性阳离子通道的通道。TRP通道家族成员可能参与神经元在接受重复刺激时的持续去极化。少

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 … More 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