Neurophysiology Laboratory, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
PLoS One. 2011;6(10):e25994. doi: 10.1371/journal.pone.0025994. Epub 2011 Oct 7.
Human immunodeficiency virus type 1 (HIV-1)-associated dementia (HAD) usually occurs late in the course of HIV-1 infection and the mechanisms underlying HAD pathogenesis are not well understood. Accumulating evidence indicates that neuronal voltage-gated potassium (Kv) channels play an important role in memory processes and acquired neuronal channelopathies in HAD. To examine whether Kv channels are involved in HIV-1-associated neuronal injury, we studied the effects of HIV-1 glycoprotein 120 (gp120) on outward K+ currents in rat cortical neuronal cultures using whole-cell patch techniques. Exposure of cortical neurons to gp120 produced a dose-dependent enhancement of A-type transient outward K+ currents (IA). The gp120-induced increase of IA was attenuated by T140, a specific antagonist for chemokine receptor CXCR4, suggesting gp120 enhancement of neuronal IA via CXCR4. Pretreatment of neuronal cultures with a protein kinase C (PKC) inhibitor, GF109203X, inhibited the gp120-induced increase of IA. Biological significance of gp120 enhancement of IA was demonstrated by experimental results showing that gp120-induced neuronal apoptosis, as detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and caspase-3 staining, was attenuated by either an IA blocker 4-aminopyridine or a specific CXCR4 antagonist T140. Taken together, these results suggest that gp120 may induce caspase-3 dependent neuronal apoptosis by enhancing IA via CXCR4-PKC signaling.
人类免疫缺陷病毒 1 型（HIV-1）相关痴呆（HAD）通常发生在 HIV-1 感染后期，HAD 发病机制的机制尚不清楚。越来越多的证据表明，神经元电压门控钾（Kv）通道在记忆过程和 HAD 中获得性神经元通道病中起重要作用。为了研究 Kv 通道是否参与 HIV-1 相关神经元损伤，我们使用全细胞膜片钳技术研究了 HIV-1 糖蛋白 120（gp120）对大鼠皮质神经元培养物外向 K+电流的影响。皮质神经元暴露于 gp120 会产生剂量依赖性增强 A 型瞬态外向 K+电流（IA）。gp120 诱导的 IA 增加被 CXCR4 的特异性拮抗剂 T140 减弱，表明 gp120 通过 CXCR4 增强神经元 IA。神经元培养物用蛋白激酶 C（PKC）抑制剂 GF109203X 预处理可抑制 gp120 诱导的 IA 增加。gp120 诱导的 IA 增强的生物学意义通过实验结果得到证明，该实验结果显示，gp120 诱导的神经元凋亡，如末端脱氧核苷酸转移酶 dUTP 缺口末端标记（TUNEL）检测和 caspase-3 染色所示，通过 IA 阻断剂 4-氨基吡啶或特异性 CXCR4 拮抗剂 T140 减弱。综上所述，这些结果表明，gp120 可能通过 CXCR4-PKC 信号增强 IA 诱导 caspase-3 依赖性神经元凋亡。
