Direct Alteration of the P/Q-Type Ca2+ Channel Property by Polyglutamine Expansion in Spinocerebellar Ataxia 6
Direct Alteration of the P/Q-Type Ca2+ Channel Property by Polyglutamine Expansion in Spinocerebellar Ataxia 6
复制标题
脊髓小脑共济失调 6 中聚谷氨酰胺扩张直接改变 P/Q 型 Ca2 通道特性
作者：
Z. Matsuyama;M. Wakamori;Y. Mori;H. Kawakami;S. Nakamura;K. Imoto
脊髓小脑性失调6 （SCA6）是由人类P/ q型Ca（2+）通道α (1A)亚基中CAG三核苷酸重复编码的聚谷氨酰胺拉伸扩张引起的。尽管SCA6与其他神经退行性谷氨酰胺重复序列疾病具有共同特征，但SCA6中的多谷氨酰胺重复序列异常小，范围在21 - 33之间。由于这种大小太小，无法形成不溶性聚集体，这被认为是导致神经退行性变的原因，因此SCA6是适合探索除聚集体形成以外的致病机制的疾病，其普遍作用受到质疑。为了描述SCA6的致病过程，我们通过分析在仓鼠肾细胞中重组表达的P/ q型Ca（2+）通道中扩展24、30或40个多聚谷氨酰胺的电流，研究了多聚谷氨酰胺扩展对通道特性的影响。含有</=24个谷氨酰胺的Ca（2+）通道表现出正常的特性，而含有30或40个谷氨酰胺的Ca（2+）通道在失活的电压依赖性下表现出8 mV的超极化位移，这大大减少了静息膜电位下的可用通道数量。结果表明，聚谷氨酰胺在SCA6中的扩增通过减少Ca（2+）流入浦肯野细胞和其他神经元而导致神经元死亡和小脑萎缩。除了广泛接受的聚谷氨酰胺拉伸通过形成聚集体发挥毒性作用的概念外，扩展的聚谷氨酰胺直接改变了受影响基因产物的功能。
Spinocerebellar ataxia 6 (SCA6) is caused by expansion of a polyglutamine stretch, encoded by a CAG trinucleotide repeat, in the human P/Q-type Ca(2+) channel alpha(1A) subunit. Although SCA6 shares common features with other neurodegenerative glutamine repeat disorders, the polyglutamine repeats in SCA6 are exceptionally small, ranging from 21 to 33. Because this size is too small to form insoluble aggregates that have been blamed for the cause of neurodegeneration, SCA6 is the disorder suitable for exploring the pathogenic mechanisms other than aggregate formation, whose universal role has been questioned. To characterize the pathogenic process of SCA6, we studied the effects of polyglutamine expansion on channel properties by analyzing currents flowing through the P/Q-type Ca(2+) channels with an expanded stretch of 24, 30, or 40 polyglutamines, recombinantly expressed in baby hamster kidney cells. Whereas the Ca(2+) channels with </=24 polyglutamines showed normal properties, the Ca(2+) channels with 30 or 40 polyglutamines exhibited an 8 mV hyperpolarizing shift in the voltage dependence of inactivation, which considerably reduces the available channel population at a resting membrane potential. The results suggest that polyglutamine expansion in SCA6 leads to neuronal death and cerebellar atrophy through reduction in Ca(2+) influx into Purkinje cells and other neurons. Besides the widely accepted notion that polyglutamine stretches exert toxic effects by forming aggregates, expanded polyglutamines directly alter functions of the affected gene product.
使用抗体包被的珠子对单个转染细胞进行电生理学视觉识别。
影响因子：
2.7
作者：
Jurman,ME;Boland,LM;Liu,Y;Yellen,G
通讯作者：
Yellen,G