Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
J Neurosci. 2012 Dec 5;32(49):17725-39. doi: 10.1523/JNEUROSCI.3029-12.2012.
The chemokine stromal cell-derived factor-1α (SDF-1α) has multiple effects on neuronal activity, survival, and death under conditions that generate a proinflammatory microenvironment within the brain, via signaling through C-X-C-type chemokine receptor 4 (CXCR4), although the underlying cellular/molecular mechanisms are unclear. Using rat hippocampal neurons, we investigated distinct modifications in the voltage-gated K⁺ (Kv) channel Kv2.1 in response to short- and long-term SDF-1α/CXCR4-mediated signaling as an underlying mechanism for CXCR4-dependent regulation of neuronal survival and death. Acute exposure of neurons to SDF-1α led to dynamic dephosphorylation and altered localization of Kv2.1 channel, resulting in enhanced voltage-dependent activation of Kv2.1-based delayed-rectifier Kv currents (I(DR)). These changes were dependent on CXCR4- and/or NMDA receptor-mediated activation of calcineurin and provide neuroprotection. However, prolonged SDF-1α treatment leads to CXCR4-mediated activation of p38 mitogen-activated protein kinase, resulting in phosphorylation of Kv2.1 at S800 and enhanced surface trafficking of the channel protein, resulting in increased I(DR)/Kv2.1 current density. This, in combination with sustained dephosphorylation-induced enhancement of the voltage-dependent activation of I(DR)/Kv2.1, predisposed neurons to excessive K⁺ efflux, a vital step for the neuronal apoptotic program. Such apoptotic death was dependent on CXCR4 and Kv2.1 function and was absent in cells expressing the Kv2.1-S800A mutant channel. Furthermore, similar modifications in Kv2.1 and CXCR4/Kv2.1-dependent apoptosis were observed following treatment of neurons with the human immunodeficiency virus-1 (HIV-1) glycoprotein gp120. Therefore, distinct modifications in Kv2.1 in response to short- and long-term CXCR4-mediated signaling could provide a basis for neuroprotection or apoptosis in neuropathologies, such as neuroinflammation, stroke, brain tumors, and HIV-associated neurodegeneration.
趋化因子基质细胞衍生因子-1α（SDF-1α）通过与其受体 C-X-C 型趋化因子受体 4（CXCR4）结合，在脑内产生促炎微环境的条件下，对神经元的活性、存活和死亡具有多种影响，但其潜在的细胞/分子机制尚不清楚。本研究使用大鼠海马神经元，研究了 SDF-1α/CXCR4 介导的信号转导对电压门控 K⁺（Kv）通道 Kv2.1 的不同修饰，作为 CXCR4 依赖性调节神经元存活和死亡的潜在机制。神经元急性暴露于 SDF-1α 导致 Kv2.1 通道的动态去磷酸化和定位改变，从而增强 Kv2.1 为基础的延迟整流 Kv 电流（I(DR)）的电压依赖性激活。这些变化依赖于 CXCR4 和/或 NMDA 受体介导的钙调神经磷酸酶激活，并提供神经保护作用。然而，长期 SDF-1α 处理导致 CXCR4 介导的 p38 丝裂原激活蛋白激酶激活，导致 Kv2.1 在 S800 处磷酸化，并增强通道蛋白的表面转运，从而增加 I(DR)/Kv2.1 电流密度。这与持续去磷酸化诱导的 I(DR)/Kv2.1 的电压依赖性激活增强相结合，使神经元易于过度 K⁺外排，这是神经元凋亡程序的一个重要步骤。这种凋亡性死亡依赖于 CXCR4 和 Kv2.1 的功能，并且在表达 Kv2.1-S800A 突变通道的细胞中不存在。此外，在神经元用人类免疫缺陷病毒-1（HIV-1）糖蛋白 gp120 处理后，也观察到 Kv2.1 和 CXCR4/Kv2.1 依赖性凋亡的类似修饰。因此，CXCR4 介导的信号转导对 Kv2.1 的不同修饰可能为神经炎症、中风、脑肿瘤和 HIV 相关神经退行性变等神经病理学中的神经保护或凋亡提供基础。
