The common inhaled anesthetic isoflurane increases aggregation of huntingtin and alters calcium homeostasis in a cell model of Huntington's disease.
The common inhaled anesthetic isoflurane increases aggregation of huntingtin and alters calcium homeostasis in a cell model of Huntington's disease.
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DOI：
10.1016/j.taap.2010.10.032
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发表时间：
2011-02-01
影响因子：
3.8
通讯作者：
Wei H
中科院分区：
文献类型：
--
作者：
Wang Q;Liang G;Yang H;Wang S;Eckenhoff MF;Wei H
已知异氟烷会增加 β-淀粉样蛋白聚集和神经元损伤。我们假设异氟醚会对聚谷氨酰胺亨廷顿蛋白产生类似的作用，并会导致细胞内钙稳态的改变。我们在扩增的谷氨酰胺亨廷顿蛋白敲入小鼠 (STHdhQ111/Q111) 和野生型 (STHdhQ7/Q7) 纹状体神经元的纹状体细胞中测试了这一假设。在存在或不存在细胞外钙以及存在或不存在xestospongin C（一种有效的内质网肌醇1,4,5-三磷酸（InsP3）受体拮抗剂）的情况下，将原代培养的神经元暴露于等量浓度的异氟醚、七氟醚和地氟醚中24小时。测量了亨廷顿蛋白的聚集、细胞活力和钙浓度。异氟醚、七氟醚和地氟醚均增加了STHdhQ111/Q111细胞中亨廷顿蛋白的聚集，其中异氟醚的作用最大。与野生型 STHdhQ7/Q7 纹状体细胞相比，异氟烷在 STHdhQ111/Q111 亨廷顿细胞中诱导内质网更多的钙释放和相对更多的细胞损伤。然而，七氟烷和地氟烷导致内质网释放的钙减少，细胞损伤也减少。 Xestospongin C 抑制异氟烷诱导的 ER 钙释放、亨廷顿蛋白聚集以及 STHdhQ111/Q111 细胞中的细胞损伤。总之，Q111 形式的亨廷顿蛋白通过对 ER IP3 受体的联合作用，增加了纹状体神经元对异氟醚神经毒性的脆弱性。内质网释放的钙有助于麻醉诱导的亨廷顿蛋白在 STHdhQ111/Q111 纹状体细胞中聚集。
Isoflurane is known to increase β-amyloid aggregation and neuronal damage. We hypothesized that isoflurane will have similar effects on the polyglutamine huntingtin protein, and will cause alterations in intracellular calcium homeostasis. We tested this hypothesis in striatal cells from the expanded glutamine huntingtin knock-in mouse (STHdhQ111/Q111) and wild type (STHdhQ7/Q7) striatal neurons. The primary cultured neurons were exposed for 24h to equipotent concentrations of isoflurane, sevoflurane and desflurane in the presence or absence of extracellular calcium and with or without xestospongin C, a potent endoplasmic reticulum inositol 1,4,5-trisphosphate (InsP3) receptor antagonist. Aggregation of huntingtin protein, cell viability, and calcium concentrations were measured. Isoflurane, sevoflurane and desflurane all increased the aggregation of huntingtin in STHdhQ111/Q111 cells, with isoflurane having the largest effect. Isoflurane induced greater calcium release from the ER and relatively more cell damage in the STHdhQ111/Q111 Huntington cells than in the wild type STHdhQ7/Q7 striatal cells. However, sevoflurane and desflurane caused less calcium release from the ER and less cell damage. Xestospongin C inhibited the isoflurane-induced calcium release from the ER, aggregation of huntingtin, and cell damage in the STHdhQ111/Q111 cells. In summary, the Q111 form of huntingtin increases the vulnerability of striatal neurons to isoflurane neurotoxicity through combined actions on the ER IP3 receptors. Calcium release from the ER contributes to the anesthetic induced huntingtin aggregation in STHdhQ111/Q111 striatal cells.
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DOI：
10.1083/jcb.141.5.1097
发表时间：
1998-06-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hackam AS;Singaraja R;Wellington CL;Metzler M;McCutcheon K;Zhang T;Kalchman M;Hayden MR
通讯作者：
Hayden MR
影响因子：
4.8
作者：
Ding, QX;Lewis, JJ;Keller, JN
通讯作者：
Keller, JN
影响因子：
8.8
作者：
Kindler, CH;Eilers, H;Bickler, PE
通讯作者：
Bickler, PE
影响因子：
8.8
作者：
Matsuoka, H;Kurosawa, S;Hashimoto, Y
通讯作者：
Hashimoto, Y
影响因子：
8.8
作者：
Liang G;Ward C;Peng J;Zhao Y;Huang B;Wei H
通讯作者：
Wei H