Polyglutamine repeats of spinocerebellar ataxia 6 impair the cell-death-preventing effect of Cav2.1 Ca2+ channel-loss-of-function cellular model of SCA6
Polyglutamine repeats of spinocerebellar ataxia 6 impair the cell-death-preventing effect of Cav2.1 Ca2+ channel-loss-of-function cellular model of SCA6
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DOI：
10.1016/j.nbd.2004.07.013
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发表时间：
2004-11-01
影响因子：
6.1
通讯作者：
Inuzuka, T
中科院分区：
文献类型：
--
作者：
Matsuyama, Z;Yanagisawa, NK;Inuzuka, T
脊髓小脑性共济失调（SCA）6是由位于人Ca（V）2.1（P/Q型）Ca 2+通道α（1）2.1亚基C-末端的CAG三核苷酸重复序列编码的多聚谷氨酰胺序列的小幅扩增引起的，表现为缓慢进行性小脑性共济失调。为了阐明SCA 6的致病机制，我们将不同长度的CAG重复序列引入Ca 2+通道α（1）2.1亚基cDNA中，并在稳定表达辅助亚基（α（2）δ和β（4））的幼仓鼠肾细胞中表达。在血清饥饿加钾诱导的去极化条件下，正常和突变型Ca 2+通道转染的细胞之间细胞死亡的发生不同，Cdk抑制更清楚地阐明了这种差异。Ca（V）2.1（P/Q型）Ca ~（2+）通道特异性阻断剂Omega-agatoxin IVA可阻断正常Ca ~（2+）通道对细胞死亡的抑制作用。与我们先前发现的SCA 6中的多聚谷氨酰胺扩增干扰Ca 2+通道以减少Ca 2+内流一起，这些结果表明突变Ca 2+通道的功能受损使得它们不能防止细胞死亡。(C)2004年爱思唯尔公司All rights reserved.
Spinocerebellar ataxia (SCA) 6 is caused by small expansion of a polyglutamine sequence, encoded by CAG trinucleotide repeats, at the C-terminal end of the human Ca(V)2.1 (P/Q-type) Ca2+ channel alpha(1)2.1 subunit and it manifests itself as slowly progressive cerebellar ataxia. To elucidate the pathogenic mechanisms underlying SCA6, we introduced CAG repeats of various lengths into the Ca2+ channel alpha(1)2.1 subunit cDNA and expressed them in baby hamster kidney cells stably expressing the auxiliary subunits (alpha(2)delta and beta(4)). The occurrence of cell death differed between cells transfected with the normal and mutant Ca2+ channels under the condition of serum starvation plus potassium-induced depolarization, and Cdk inhibition elucidated the differences more clearly. The Ca(V)2.1 (P/Q-type) Ca2+ channel-specific blocker omega-agatoxin IVA abolished the cell-death-preventing effect of the normal Ca2+ channel. Together with our previous finding that the polyglutamine expansion in SCA6 interferes with the Ca2+ channel to reduce Ca2+ influx, these results indicate that impaired function of the mutant Ca2+ channels rendered them unable to prevent cell death. (C) 2004 Elsevier Inc. All rights reserved.