Voltage-gated potassium channels in human immunodeficiency virus type-1 (HIV-1)-associated neurocognitive disorders

Abstract

Human immunodeficiency virus type-1 (HIV-1)-associated dementia (HAD), a severe form of HIV-associated neurocognitive disorders (HAND), describes the cognitive impairments and behavioral disturbances which afflict many HIV-infected individuals. Although the precise mechanism leading to HAD is incompletely understood, it is commonly accepted its progression involves a critical mass of infected and activated mononuclear phagocytes (brain perivascular macrophages and microglia) releasing immune and viral products in the brain. These cellular and viral products induce neuronal dysfunction and injury via various signaling pathways. Emerging evidence indicates voltage-gated potassium (K(v)) channels, key regulators of cell excitability and animal behavior (learning and memory), are involved in the pathogenesis of HAD/HAND. Here we survey the literature and find that HAD-related alterations in cellular and viral products can increase neuronal K(v) channel activity, leading to neuronal dysfunction and cognitive deficits. Thus, neuronal K(v) channels may be a new target in the effort to develop therapies for HAD and perhaps other inflammatory neurodegenerative disorders.

Fig. 1

Effects of soluble factors on the voltage-gated K⁺ currents of neurons. This diagram summarizes the effects of identified cytokines, arachidonic acid, glutamate, viral protein, and unidentified factors in macrophage-conditioned media. I_A, A-type K⁺ current; I_K, delayed rectifier K⁺ current. *Unpublished data

Fig. 2

Macrophage-conditioned media induces neuronal injury through the activation of neuronal K_v channels. a An example of the outward delayed rectifier K⁺ current recorded from a cultured rat hippocampal neuron in the presence of a 5-mM 4-AP. The cell was held at −60 mV, stepped to −40 mV, and followed by the steps of 10-mV increments. Bath application of the lipopolysaccharide-stimulated macrophage-conditioned media (MCM+, 1:30 dilution) produced a reversible increase in an outward delayed rectifier K⁺ current. b A summary graph illustrating the MCM+ significantly increases the outward delayed rectifier K⁺ current in cultured hippocampal neurons and its blockade by a TEA (n=10). c Neurotoxic activity produced by the MCM+ in hippocampal neuronal cultures. TEA, a K_v channel antagonist, protected neurons against MCM-induced neurotoxicity. Neuronal injury was assessed after 24-h treatments with MCM+ by staining with a membrane-impermeable DNA-binding dye PI (Molecular Probes, Eugene, OR, USA) and counterstaining with a membrane-permeable DAPI. Note that MCM+ produced significant neuronal injury (in red) and TEA treatment blocked MCM-associated neuronal injury, suggesting the activation of K_v channels plays a crucial role in MCM-associated neuronal injury. d A summary data derived from c (n=36). The survival rates were calculated by counting the numbers of cells from the five different visual fields in each neuronal culture dish treated with DAPI (blue) and PI dyes (red). *p<0.05 vs. control, #p<0.05 vs. MCM+