The weaver Mutation Causes a Loss of Inward Rectifier Current Regulation in Premigratory Granule Cells of the Mouse Cerebellum
The weaver Mutation Causes a Loss of Inward Rectifier Current Regulation in Premigratory Granule Cells of the Mouse Cerebellum
复制标题
织布者突变导致小鼠小脑迁移前颗粒细胞内向整流电流调节丧失
作者：
P. Rossi;G. de Filippi;Simona Armano;V. Taglietti;E. D’Angelo
最近人们对 theweaver 突变产生了极大的兴趣，这种突变会导致内向整流通道改变，从而导致小鼠神经元分化严重受损和严重运动功能障碍（Hess，1996）。突变的主要目标是小脑颗粒细胞，其中大多数无法分化并在迁移前位置退化（Rakic 和 Sidman，1973a，b）。已经提出了两个假设来解释突变型内向整流通道的致病作用：即内向整流通道活性要么缺乏（Surmeier等，1996），要么改变（Kofuji等，1996；Silverman等，1996；Slesinger等，1996）。我们通过记录野生型和织布突变小鼠不同发育阶段小脑颗粒细胞的内向整流电流来研究这个问题。在野生型小鼠中，随着颗粒细胞从迁移前阶段发展到迁移后阶段，内向整流电流从G蛋白依赖性激活转变为组成型激活。在 weaver 突变小鼠中，迁移前颗粒细胞中不存在 G 蛋白依赖性内向整流电流。处于迁移后位置的假定颗粒细胞群表达组成型内向整流电流，其特性与异源系统中表达的突变 GIRK2 通道兼容。由于颗粒细胞在迁移前阶段退化（Smeyne 和 Goldowitz，1989），内向整流电流的丧失及其对膜电位的调节可能在织布神经元变性的发病机制中发挥关键作用。
Considerable interest has recently focused on theweaver mutation, which causes inward rectifier channel alterations leading to profound impairment of neuronal differentiation and to severe motor dysfunction in mice (Hess, 1996). The principal targets of mutation are cerebellar granule cells, most of which fail to differentiate and degenerate in a premigratory position (Rakic and Sidman, 1973a,b). Two hypotheses have been put forward to explain the pathogenetic role of mutant inward rectifier channels: namely that inward rectifier channel activity is either lacking (Surmeier et al., 1996) or altered (Kofuji et al., 1996; Silverman et al., 1996;Slesinger et al., 1996). We have examined this question by recording inward rectifier currents from cerebellar granule cells in situ at different developmental stages in wild-type and weaver mutant mice. In wild-type mice, the inward rectifier current changed from a G-protein-dependent activation to a constitutive activation as granule cells developed from premigratory to postmigratory stages. In weaver mutant mice, G-protein-dependent inward rectifier currents were absent in premigratory granule cells. A population of putative granule cells in the postmigratory position expressed a constitutive inward rectifier current with properties compatible with mutated GIRK2 channels expressed in heterologous systems. Because granule cells degenerate at the premigratory stage (Smeyne and Goldowitz, 1989), the loss of inward rectifier current and its regulation of membrane potential are likely to play a key role in the pathogenesis of weaver neuronal degeneration.
DOI：
10.1073/pnas.92.14.6542
发表时间：
1995-07-03
影响因子：
11.1
作者：
KOFUJI, P;DAVIDSON, N;LESTER, HA
通讯作者：
LESTER, HA
通过韦弗钾通道的离子通量的再生联系是突变病理生理学的基础。
DOI：
10.1073/pnas.93.26.15429
发表时间：
1996
影响因子：
11.1
作者：
Silverman,SK;Kofuji,P;Dougherty,DA;Davidson,N;Lester,HA
通讯作者：
Lester,HA
GIRK2 的 Weaver 突变导致小脑颗粒细胞内向整流 K 电流丧失。
DOI：
10.1073/pnas.93.20.11191
发表时间：
1996
影响因子：
11.1
作者：
Surmeier,DJ;Mermelstein,PG;Goldowitz,D
通讯作者：
Goldowitz,D