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Characterization of neurological CaィイD12+ィエD1 channel mutant mice.

神经学 CaiD12+D1 通道突变小鼠的表征。

基本信息

批准号：
10680755
负责人：
MORI Yasuo
金额：
$ 2.11万
依托单位：
National Institute for Physiological Sciences
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

P/Q-type voltage-dependent CaィイD12+ィエD1 channels are markedly abundant in the nervous system. We have characterized functional abnormality of the P/Q-type channels elicited by the αィイD21AィエD2,. mutations, tottering (tg) and leaner (tgィイD1laィエD1). Comparison of properties of the native and recombinant mutant channels suggests that single tottering mutations are directly responsible for the neuropathic phenotypes of reduction in current density and deviations in gating behavior, which lead to neuronal death and cerebellar atrophy. The ataxic mouse mutation, rolling Nagoya (tgィイD1rolィエD1), in the αィイD21AィエD2, gene leads to a charge-neutralizing arginine-to-glycine substitution at position 1262 in the voltage sensor-forming segment S4 in repeat III. Functional changes induced by the tgィイD1rolィエD1 mutation in the recombinant αィイD21AィエD2 channel indicate that a gating charge defect in the voltage sensor of P/Q-type CaィイD12+ィエD1 channels is the direct consequence of the tgィイD1rolィエD1 mutation … More . Furthermore, in tgィイD1rolィエD1 mice, the abnormal P-type channel significantly impairs integrative properties of Purkinje neurons, resulting in locomotor deficits.Spinocerebellar ataxia 6 (SCA6) is caused by expansion of a polyglutamine stretch, encoded by a CAG trinucleotide repea1 in the human P/Q type CaィイD12+ィエD1 channel αィイD21AィエD2 subunit. The CaィイD12+ィエD1 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 strongly suggest that polyglutamine expansion in SCA6 leads to neuronal death and cerebellar atrophy through reduction in CaィイD12+ィエD1 influx into Purkinje cells and other neurons, besides the widely accepted notion that polyglutamine stretches exert toxic effects by forming aggregates.Our research also provided evidence that cytoplasmic loop between repeats II and III of N-type channels is a regulatory site for Gβγ and the C-termini of P/Q and N-types for Gα. Less

P/Q型电压依赖性Ca ~（2+）D_12 + Ca ~（2+）D_1通道在神经系统中非常丰富。本实验对α-淀粉样蛋白D21 A受体D2、..引起的P/Q通道功能异常进行了表征。突变，蹒跚（tg）和更瘦（tg蹒跚D1 la蹒跚D1）。天然和重组突变体通道的性质的比较表明，单一的摇摇欲坠的突变是直接负责的神经病理性表型的电流密度降低和偏差的门控行为，导致神经元死亡和小脑萎缩。共济失调小鼠突变，滚名古屋（tg精氨酸D1 rol精氨酸D1），在α精氨酸D21 A精氨酸D2基因中，导致重复序列III中电压传感器形成片段S4的位置1262处的电荷中和精氨酸-甘氨酸取代。由重组α β-D_（21）A β-D_（12）D_2通道中tg β-D_（1）rol β-D_（1）突变引起的功能变化表明，P/Q型Ca β-D_（12）+ β-D_（1）通道电压传感器中的门控电荷缺陷是tg β-D_（1）rol β-D_（1）突变的直接结果 ...更多信息 .脊髓小脑性共济失调6型（SCA 6）是由人P/Q型Ca ~（2+）通道α β D_21A β D_2亚基中CAG三核苷酸重复序列1编码的多聚谷氨酰胺链的扩增引起的。具有30或40个聚谷氨酰胺的Ca ~（2+）D12+ Ca ~（2+）D1通道在失活的电压依赖性中表现出8 mV的超极化移位，这大大减少了静息膜电位下可用的通道群。结果强烈表明，SCA 6中的多聚谷氨酰胺扩增通过减少Ca ~（2+）D12+ Ca ~（2+）D1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，我们的研究还证明了N型通道重复序列II和III之间的胞浆环是G β γ和C-谷氨酰胺的调节位点，并证明了N型通道重复序列II和III之间的胞浆环是Gβγ和C-谷氨酰胺的调节位点。Gα的P/Q和N型末端。少

项目成果

期刊论文数量（40）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Furukawa T: "Differential interactions of the C terminus and the cytoplasmic I-II loop of neuronal Ca^<2+> channels with G-protein α and β γ subunits. I. molecular determination." J Biol Chem. 273. 17585-17594 (1998)

Furukawa T：“神经元 Ca^2+ 通道的 C 末端和细胞质 I-II 环与 G 蛋白 α 和 β γ 亚基的不同相互作用。I. 分子测定。”273。17585- 17594 (1998)

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

Felix R, Biddlecome GH, Arikkath J, Mahaffey CL, Valenzuela A, Bartlett II FS, Mori Y, Campbell KP & Frankel WN: "The mouse stargazer gene encodes a neuronal CaィイD12+ィエD1 channel γ subunit."Nature Genetics (Article). 19. 340-347 (1998)

Felix R、Biddlecome GH、Arikkath J、Mahaffey CL、Valenzuela A、Bartlett II FS、Mori Y、Campbell KP 和 Frankel WN：“小鼠观星者基因编码神经元 CaD12+D1 通道 γ 亚基。”《自然遗传学》（文章）。 19. 340-347 (1998)