Properties of human Cav2.1 channel with a spinocerebellar ataxia type 6 mutation expressed in Purkinje cells
Properties of human Cav2.1 channel with a spinocerebellar ataxia type 6 mutation expressed in Purkinje cells
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DOI：
10.1016/j.mcn.2006.11.006
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发表时间：
2007-02-01
影响因子：
3.5
通讯作者：
Tanabe, Tsutomu
中科院分区：
文献类型：
--
作者：
Saegusa, Hironao;Wakamori, Minoru;Tanabe, Tsutomu
脊髓小脑共济失调 6 型 (SCA6) 是由 P/Q 型 Ca2+ 通道 (Ca(v)2.1) 中的聚谷氨酰胺扩张引起的，其特征是小脑浦肯野细胞主要变性。为了表征小脑浦肯野细胞中具有 SCA6 突变的 Ca(v)2.1 通道，我们构建了表达具有 28 个聚谷氨酰胺重复序列（疾病范围）和 13 个聚谷氨酰胺重复序列（正常范围）的人 Ca(v)2.1 的敲入小鼠模型。来自纯合对照或 SCA6 敲入小鼠的浦肯野细胞的膜片钳记录显示出对蜘蛛毒素 omega-Agatoxin IVA 高度敏感的非失活电流，表明浦肯野细胞中表达的人 Ca(v)2.1 在培养细胞系中表达时表现出典型的 P 型特性，与之前显示的 Q 型特性的数据形成鲜明对比。此外，激活和失活的电压依赖性以及电流密度在SCA6和对照之间没有差异，尽管这些特性在之前使用非神经元细胞作为表达系统的报告中发生了改变。因此，我们的结果并不支持通道特性的改变可能是 SCA6 致病机制的基础这一观点。 (c) 2006 Elsevier Inc. 保留所有权利。
Spinocerebellar ataxia type 6 (SCA6) is caused by polyglutamine expansion in P/Q-type Ca2+ channels (Ca(v)2.1) and is characterized by predominant degeneration of cerebellar Purkinje cells. To characterize the Ca(v)2.1 channel with an SCA6 mutation in cerebellar Purkinje cells, we have generated knock-in mouse models that express human Ca(v)2.1 with 28 polyglutamine repeats (disease range) and with 13 polyglutamine repeats (normal range). Patch-clamp recordings of the Purkinje cells from homozygous control or SCA6 knock-in mice revealed a non-inactivating current that is highly sensitive to a spider toxin omega-Agatoxin IVA, indicating that the human Ca(v)2.1 expressed in Purkinje cells exhibits typical P-type properties in contrast to the previous data showing Q-type properties, when it was expressed in cultured cell lines. Furthermore, the voltage dependence of activation and inactivation and current density were not different between SCA6 and control, though these properties were altered in previous reports using non-neuronal cells as expression systems. Therefore, our results do not support the notion that the alteration of the channel properties may underlie the pathogenic mechanism of SCA6. (c) 2006 Elsevier Inc. All rights reserved.