Potential independent action of sigma receptor ligands through inhibition of the Kv2.1 channel.
Potential independent action of sigma receptor ligands through inhibition of the Kv2.1 channel.
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西格玛受体配体通过抑制 Kv2.1 通道的潜在独立作用
DOI：
10.18632/oncotarget.19581
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发表时间：
2017-08-29
期刊：
影响因子：
--
通讯作者：
Pattnaik BR
中科院分区：
文献类型：
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作者：
Liu X;Fu Y;Yang H;Mavlyutov T;Li J;McCurdy CR;Guo LW;Pattnaik BR
sigma-1受体（σ1-R）和sigma-2受体（σ2-R）是治疗癌症、疼痛、抑郁症、视网膜变性和其他神经元疾病的潜在药物靶标。以往的研究表明，sigma-1受体调节多个通道的活动。我们感兴趣的是可能的西格玛受体调制Kv2.1，丰富的视网膜光感受器中的K+通道。我们测试了建立的σ受体配体对在HEK 293细胞中稳定表达的Kv2.1通道的作用。令人惊讶的是，在我们使用CRISPR/Cas9技术工程化的野生型和σ1-R敲除HEK 293细胞中，σ1-R拮抗剂抑制Kv2.1电流。此外，σ1-R拮抗剂和σ2-R激动剂PB 28在σ1-R敲除细胞中抑制Kv2.1，但这种作用不被对Kv2.1没有影响的σ2-R拮抗剂阻断。我们还观察到PB 28在野生型以及σ1-R敲除小鼠中对视网膜电图的抑制。因此，本研究的结果表明，σ配体的Kv2.1抑制功能不是σ受体依赖性的，表明这些配体对Kv2.1通道的直接作用。
The sigma-1 receptor (σ1-R) and sigma-2 receptor (σ2-R) are potential drug targets for treatment of cancer, pain, depression, retinal degeneration and other neuronal diseases. Previous reports show that sigma-1 receptor modulates the activities of multiple channels. We are interested in possible sigma receptor modulation of Kv2.1, a K+ channel abundant in retinal photoreceptors. We tested the effect of established sigma receptor ligands on Kv2.1 channels which were stably expressed in HEK293 cells. Surprisingly, σ1-R antagonists inhibited Kv2.1 currents in both wild type and σ1-R knockout HEK293 cells that we engineered using the CRISPR/Cas9 technology. Moreover, PB28, a σ1-R antagonist and also σ2-R agonist, inhibited Kv2.1 in σ1-R knockout cells, but this action was not blocked by the σ2-R antagonists that did not have an effect on Kv2.1. We also observed inhibition of electroretinogram by PB28 in wild type as well as σ1-R knockout mice. Thus, the results in this study indicate that the Kv2.1-inhibiting function of the sigma ligands is not sigma receptor dependent, suggesting a direct effect of these ligands on the Kv2.1 channel.