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Abstract
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.
Highlights
Human immunodeficiency virus type 1 (HIV-1)-infected individuals often suffer from neurological complications such as memory loss, mental slowing, and gait disturbance [1]
Our results demonstrated that gp120 increased 4-aminopyridine (4-action potentials (AP))-sensitive, A-type transient outward K+ currents (IA) leading to neuronal apoptosis in rat cortical neuronal cultures
To investigate whether the gp120-mediated enhancement of IA contributes to gp120induced neuronal injury, we examined the protective effects of 4AP on gp120-induced neuronal apoptosis in rat cortical neuronal cultures
Summary
Human immunodeficiency virus type 1 (HIV-1)-infected individuals often suffer from neurological complications such as memory loss, mental slowing, and gait disturbance [1]. To model its effects in the CNS, gp120 was introduced into neuronal cultures and found to induce neuronal apoptosis [9,10] even at very low concentrations [11]. This in vitro gp120-mediated apoptosis was confirmed with ex vivo organotypic hippocampal slice preparations [12], transgenic over-expression of glial gp120 [13,14], and direct stereotactic intracranial injection [15,16]. While research into the apoptotic pathways downstream of gp120 binding continue, new insights into the process of apoptosis are being made, in particular with regard to the crucial role of voltage-gated potassium (Kv) channels
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