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Pathogenic mechanism of calcium channelopathy

钙离子通道病的发病机制

基本信息

批准号：
15300121
负责人：
TANABE Tsutomu
金额：
$ 10.43万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15300121/
关键词：
Spinocerebellar ataxia type 6 P-type calcium channel Purkinje cell Ca current polyglutamine disease SCA6 Cav2 channel knock-in mouse FHM EA2

项目摘要

Spinocerebellar ataxia type 6 (SCA6) is caused by polyglutamine expansion in P-type Ca channel and is characterized by predominant degeneration of cerebellar Purkinje cell. Although clinical and pathological features of each polyglutamine disease diverse widely, a common mechanism is presumed to underlie the pathogenesis inducing cytotoxicity. Polyglutamine expansion in SCA6 is within the normal range in other disease. Thus a different idea that functional alteration of the P-type Ca channel is causally related to pathophysiology of SCA6 has been emerged. Consistent with this idea several reports have been published showing SCA6 mutation induces alteration of channel properties. But these studies have been done using the non-neuronal cells. To characterize SCA6 mutation of P-type Ca channel in neuron especially in Purkinje cells, we have generated knock-in mouse models that express human P-type Ca^<2+> channel with SCA6 mutation. Patch-clamp recordings of the Purkinje cells from homozygous normal or SCA6 knock-in mice showed no alteration of channel properties by the SCA6 mutation. Thus SCA6 has been considered as one of channelopathies rather than a polyglutamine disease, our present results favors the idea that SCA6 is rather a polyglutamine disease. Therefore it may be important to explore the mechanism underlying SCA6 from the point of view of polyglutamine disease.In line with this consideration, we have tested whether SCA6 mutation affects the channel localization. When using the primary cultured hippocampal neurons, SCA6 mutation did not modify the channel localization. Then we are currently conducting this study using cerebellar Purkinje cells.

脊髓小脑性共济失调6型（SCA6）是由p型Ca通道的聚谷氨酰胺扩张引起的，以小脑浦肯野细胞变性为主。尽管每种聚谷氨酰胺疾病的临床和病理特征差异很大，但有一个共同的机制被认为是诱发细胞毒性的发病机制的基础。在其他疾病中，sc6中的聚谷氨酰胺扩增在正常范围内。因此，出现了一种不同的观点，即p型Ca通道的功能改变与SCA6的病理生理有因果关系。与这一观点一致的是，已经发表的一些报告显示，SCA6突变诱导通道性质的改变。但这些研究是用非神经元细胞完成的。为了表征神经元特别是浦肯野细胞中p型Ca通道的SCA6突变，我们建立了表达具有SCA6突变的人p型Ca^<2+>通道的敲入小鼠模型。来自纯合子正常或SCA6敲入小鼠的浦肯野细胞的膜片钳记录显示，SCA6突变没有改变通道特性。因此，sc6被认为是一种通道病而不是一种聚谷氨酰胺疾病，我们目前的结果支持sc6是一种聚谷氨酰胺疾病的观点。因此，从多聚谷氨酰胺疾病的角度探讨SCA6的机制可能很重要。基于这一考虑，我们测试了SCA6突变是否会影响通道定位。当使用原代培养的海马神经元时，SCA6突变未改变通道定位。然后我们目前正在使用小脑浦肯野细胞进行这项研究。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Kurihara, T., Nonaka, T., Tanabe, T.: "Acetic acid-conditioning stimulus induces long-lasting antinociception of somatic inflammatory pain."Pharmacol.Biochem.Behavior.. 74. 841-849 (2003)

Kurihara, T.、Nonaka, T.、Tanabe, T.：“乙酸调节刺激可诱导躯体炎症疼痛的持久抗伤害作用。”Pharmacol.Biochem.Behavior.. 74. 841-849 (2003)

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

Acetic acid conditioning stimulus induces long-lasting antinociception of somatic inflammatory pain

DOI：
10.1016/s0091-3057(03)00014-5
发表时间：
2003-03-01
期刊：
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
影响因子：
3.6
作者：
Kurihara, T;Nonaka, T;Tanabe, T
通讯作者：
Tanabe, T

The carboxy-terminal tail region of human Ca_v2.1 (P/Q-type) channel is not an essential determinant for its subcellular localization in cultured neurons

人 Ca_v2.1（P/Q 型）通道的羧基末端尾区并不是其在培养神经元中亚细胞定位的重要决定因素

DOI：
发表时间：
2005
期刊：
Genes to Cells 10
影响因子：
0
作者：
Hu;Q.et al.
通讯作者：
Q.et al.

Leukemia Inhibitory Factor Activates Cardiac L-Type Ca2+ Channels via Phosphorylation of Serine 1829 in the Rabbit Cav1.2 Subunit

DOI：
10.1161/01.res.0000126405.38858.bc
发表时间：
2004-05
期刊：
Circulation Research: Journal of the American Heart Association
影响因子：
0
作者：
E. Takahashi;K. Fukuda;S. Miyoshi;M. Murata;Takahiro Kato;M. Ita;T. Tanabe;S. Ogawa
通讯作者：
E. Takahashi;K. Fukuda;S. Miyoshi;M. Murata;Takahiro Kato;M. Ita;T. Tanabe;S. Ogawa

Genetic Approaches to the Elucidation of Calcium Channel Functions In Vivo. In "Calcium channel Pharmacology"(S. McDonough ed)

阐明体内钙通道功能的遗传学方法。