HIV-1 Tat Protein Increases Microglial Outward K+ Current and Resultant Neurotoxic Activity
Open Access
- 30 May 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (5), e64904
- https://doi.org/10.1371/journal.pone.0064904
Abstract
Microglia plays a crucial role in the pathogenesis of HIV-1-associated neurocognitive disorders. Increasing evidence indicates the voltage-gated potassium (Kv) channels are involved in the regulation of microglia function, prompting us to hypothesize Kv channels may also be involved in microglia-mediated neurotoxic activity in HIV-1-infected brain. To test this hypothesis, we investigated the involvement of Kv 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 Kv1.3 channel expression. Suppression of microglial Kv1.3 channel activity, either with Kv1.3 channel blockers Margatoxin, 5-(4-Phenoxybutoxy)psoralen, or broad-spectrum K+ channel blocker 4-Aminopyridine, or by knockdown of Kv1.3 expression via transfection of microglia with Kv1.3 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 Kv1.3 were investigated and enhancement of microglial Kv1.3 was found to correspond with an increase in Erk1/2 mitogen-activated protein kinase activation. These data suggest targeting microglial Kv1.3 channels may be a potential new avenue of therapy for inflammation-mediated neurological disorders.Keywords
This publication has 59 references indexed in Scilit:
- Involvement of Kv1.3 and p38 MAPK signaling in HIV-1 glycoprotein 120-induced microglia neurotoxicityCell Death & Disease, 2012
- HIV‐1 gp120 enhances outward potassium current via CXCR4 and cAMP‐dependent protein kinase a signaling in cultured rat microgliaGlia, 2011
- HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapyNeurology, 2010
- Predominant Functional Expression of Kv1.3 by Activated Microglia of the Hippocampus after Status epilepticusPLOS ONE, 2009
- 4-Aminopyridine Improves Spatial Memory in a Murine Model of HIV-1 EncephalitisJournal of Neuroimmune Pharmacology, 2009
- Monocyte Chemotactic Protein-1 Regulates Voltage-Gated K+ Channels and Macrophage TransmigrationJournal of Neuroimmune Pharmacology, 2008
- Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseasesProceedings of the National Academy of Sciences, 2006
- Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virusVirus Research, 2005
- HIV‐1 tat protein induces a migratory phenotype in human fetal microglia by a CCL2 (MCP‐1)‐dependent mechanism: Possible role in NeuroAIDSGlia, 2004
- Distinct types of diffuse large B-cell lymphoma identified by gene expression profilingNature, 2000