HIV-1 Tat Protein Increases Microglial Outward K+ Current and Resultant Neurotoxic Activity

Microglia plays a crucial role in the pathogenesis of HIV-1-associated neurocognitive disorders. Increasing evidence indicates the voltage-gated potassium (K v ) channels are involved in the regulation of microglia function, prompting us to hypothesize K v channels may also be involved in microglia-mediated neurotoxic activity in HIV-1-infected brain. To test this hypothesis, we investigated the involvement of K v channels in the response of microglia to HIV-1 Tat protein. Treatment of rat microglia with HIV-1 Tat protein (200 ng/ml) resulted in pro-inflammatory microglial activation, as indicated by increases in TNF-α, IL-1β, reactive oxygen species, and nitric oxide, which were accompanied by enhanced outward K + current and K v 1.3 channel expression. Suppression of microglial K v 1.3 channel activity, either with K v 1.3 channel blockers Margatoxin, 5-(4-Phenoxybutoxy)psoralen, or broad-spectrum K + channel blocker 4-Aminopyridine, or by knockdown of K v 1.3 expression via transfection of microglia with K v 1.3 siRNA, was found to abrogate the neurotoxic activity of microglia resulting from HIV-1 Tat exposure. Furthermore, HIV-1 Tat-induced neuronal apoptosis was attenuated with the application of supernatant collected from K + channel blocker-treated microglia. Lastly, the intracellular signaling pathways associated with K v 1.3 were investigated and enhancement of microglial K v 1.3 was found to correspond with an increase in Erk1/2 mitogen-activated protein kinase activation. These data suggest targeting microglial K v 1.3 channels may be a potential new avenue of therapy for inflammation-mediated neurological disorders.