Neurophysiology Laboratory, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
Cell Death Dis. 2012 Jan 19;3(1):e254. doi: 10.1038/cddis.2011.140.
Inflammatory responses mediated by activated microglia play a pivotal role in the pathogenesis of human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders. Studies on identification of specific targets to control microglia activation and resultant neurotoxic activity are imperative. Increasing evidence indicate that voltage-gated K(+) (K(v)) channels are involved in the regulation of microglia functionality. In this study, we investigated K(v)1.3 channels in the regulation of neurotoxic activity mediated by HIV-1 glycoprotein 120 (gp120)-stimulated rat microglia. Our results showed treatment of microglia with gp120 increased the expression levels of K(v)1.3 mRNA and protein. In parallel, whole-cell patch-clamp studies revealed that gp120 enhanced microglia K(v)1.3 current, which was blocked by margatoxin, a K(v)1.3 blocker. The association of gp120 enhancement of K(v)1.3 current with microglia neurotoxicity was demonstrated by experimental results that blocking microglia K(v)1.3 attenuated gp120-associated microglia production of neurotoxins and neurotoxicity. Knockdown of K(v)1.3 gene by transfection of microglia with K(v)1.3-siRNA abrogated gp120-associated microglia neurotoxic activity. Further investigation unraveled an involvement of p38 MAPK in gp120 enhancement of microglia K(v)1.3 expression and resultant neurotoxic activity. These results suggest not only a role K(v)1.3 may have in gp120-associated microglia neurotoxic activity, but also a potential target for the development of therapeutic strategies.
激活的小胶质细胞介导的炎症反应在人类免疫缺陷病毒 1 型 (HIV-1) 相关神经认知障碍的发病机制中起关键作用。研究确定控制小胶质细胞激活和由此产生的神经毒性活性的特定靶点是至关重要的。越来越多的证据表明，电压门控 K(+) (K(v)) 通道参与了小胶质细胞功能的调节。在这项研究中，我们研究了 K(v)1.3 通道在 HIV-1 糖蛋白 120 (gp120) 刺激的大鼠小胶质细胞介导的神经毒性活性调节中的作用。我们的结果表明，gp120 处理小胶质细胞会增加 K(v)1.3 mRNA 和蛋白的表达水平。同时，全细胞膜片钳研究显示，gp120 增强了小胶质细胞 K(v)1.3 电流，而 K(v)1.3 阻断剂 margatoxin 则阻断了该电流。实验结果表明，gp120 增强 K(v)1.3 电流与小胶质细胞神经毒性之间存在关联，即阻断小胶质细胞 K(v)1.3 可减弱 gp120 相关的小胶质细胞产生神经毒素和神经毒性。通过用 K(v)1.3-siRNA 转染小胶质细胞来敲低 K(v)1.3 基因，可消除 gp120 相关的小胶质细胞神经毒性活性。进一步的研究揭示了 p38 MAPK 参与了 gp120 增强小胶质细胞 K(v)1.3 表达和由此产生的神经毒性活性。这些结果不仅表明 K(v)1.3 在 gp120 相关的小胶质细胞神经毒性活性中可能具有作用，而且还表明其可能成为治疗策略的潜在靶点。
