Sigma-1 receptor alters the kinetics of Kv1.3 voltage gated potassium channels but not the sensitivity to receptor ligands.
Sigma-1 receptor alters the kinetics of Kv1.3 voltage gated potassium channels but not the sensitivity to receptor ligands.
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DOI：
10.1016/j.brainres.2012.02.070
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发表时间：
2012-05-03
期刊：
影响因子：
2.9
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Kinoshita M;Matsuoka Y;Suzuki T;Mirrielees J;Yang J
Sigma 1受体（Sigma 1 R）是细胞内伴侣蛋白，其结合精神药物以及临床上使用的药物，如氯胺酮和氟哌啶醇。据报道，Sigma 1 R的共表达增强了几种电压门控离子通道对Sigma 1 R配体的敏感性。Kv1.3是T淋巴细胞中表达的主要电压门控钾通道，在免疫激活中具有记录的作用。为了更好地了解Sigma 1 R对Kv离子通道的调节，我们研究了Sigma 1 R共表达对非洲爪蟾卵母细胞中表达的离子通道中Kv1.3生理学和药理学的影响。我们还探讨了蛋白质的Kv1.3和Sigma 1 R之间的蛋白质相互作用所必需的Kv1.3的蛋白质结构域，通过免疫共沉淀研究。缓慢失活外向电流与Kv1.3的表达一致，引起阶跃去极化。当与Sigma 1 R共表达时，由Erev、V1/2和斜率因子表征的电流保持不变。失活时间常数的分析显示，当与Sigma 1 R共表达时，Kv1.3电流衰减更快。然而，与之前报道的密切相关的Kv1.4和Kv1.5电压门控钾通道中配体敏感性的调节相反，当与Sigma 1 R共表达时，对Sigma 1 R配体的敏感性保持不变。各种Kv1.3截短构建体的免疫共沉淀分析表明，Kv1.3蛋白的跨膜结构域负责与Sigma 1 R的蛋白质：蛋白质相互作用。Sigma 1 R可能与Kv离子通道家族蛋白的不同结构域相互作用，导致不同通道的不同调节。
Sigma1 receptors (Sigma1R) are intracellular chaperone proteins that bind psychotropic drugs and also clinically used drugs such as ketamine and haloperidol. Co-expression of the Sigma1R has been reported to enhance the sensitivity of several voltage-gated ion channels to Sigma1R ligands. Kv1.3 is the predominant voltage-gated potassium channel expressed in T lymphocytes with a documented role in immune activation. To gain a better understanding of Sigma1R modulation of Kv ion channels, we investigated the effects of Sigma1R co-expression on Kv1.3 physiology and pharmacology in ion channels expressed in Xenopus oocytes. We also explored the protein domains of Kv1.3 necessary for protein:protein interaction between Kv1.3 and Sigma1R through co-immunoprecipitation studies. Slowly inactivating outward-going currents consistent with Kv1.3 expression were elicited on step depolarizations. The current characterized by Erev, V1/2, and slope factor remained unchanged when co-expressed with Sigma1R. Analysis of inactivation time constant revealed a faster Kv1.3 current decay when co-expressed with Sigma1R. However the sensitivity to Sigma1R ligands remained unaltered when co-expressed with the Sigma1R in contrast to the previously reported modulation of ligand sensitivity in closely related Kv1.4 and Kv1.5 voltage gated potassium channels. Co-immunoprecipitation assays of various Kv1.3 truncation constructs indicated that the transmembrane domain of the Kv1.3 protein was responsible for the protein:protein interaction with the Sigma1R. Sigma1R likely interacts with different domains of Kv ion channel family proteins resulting in distinct modulation of different channels.
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影响因子：
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